Materiały źródłowe

• #1 Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis – Parkinson’s Disease – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536722/

  Parkinsons disease (PD) is a common neurodegenerative disorder. […] The cause of PD is not known, but a number of genetic risk factors have now been characterized, as well as several genes which cause rare familial forms of PD. […] Several processes have been implicated in PD, including mitochondrial dysfunction, defective protein clearance mechanisms, and neuroinflammation, but the way in which these factors interact remains incompletely understood. […] A number of mechanisms have been implicated in PD pathogenesis, with -synuclein aggregation central to the development of the disease. […] Multiple other processes are thought to be involved, with several studies suggesting that abnormal protein clearance, mitochondrial dysfunction, and neuroinflammation play a role in the onset and progression of PD. […] However, the relationship between these pathways remains unclear.

• #2 Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-023-01353-3

  Parkinsons disease (PD) is the second most common neurodegenerative disease worldwide, and its treatment remains a big challenge. The pathogenesis of PD may be related to environmental and genetic factors, and exposure to toxins and gene mutations may be the beginning of brain lesions. The identified mechanisms of PD include -synuclein aggregation, oxidative stress, ferroptosis, mitochondrial dysfunction, neuroinflammation, and gut dysbiosis. The interactions among these molecular mechanisms complicate the pathogenesis of PD and pose great challenges to drug development. […] Most conventional therapeutic interventions for PD possess limited effects and have serious side effects, heightening the need to develop novel treatments for this disease. In this review, we systematically summarized the pathogenesis, especially the molecular mechanisms of PD, the classical research models, clinical diagnostic criteria, and the reported drug therapy strategies, as well as the newly reported drug candidates in clinical trials.

• #3 Parkinson’s disease: etiopathogenesis and treatment | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/91/8/795

  The concept of idiopathic Parkinsons disease (PD) as a single entity has been challenged with the identification of several clinical subtypes, pathogenic genes and putative causative environmental agents. […] The key molecular pathogenic mechanisms include -synuclein misfolding and aggregation, mitochondrial dysfunction, impairment of protein clearance (associated with deficient ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress. […] The involvement of dopaminergic as well as noradrenergic, glutamatergic, serotonergic and adenosine pathways provide insights into the rich and variable clinical phenomenology associated with PD and the possibility of alternative therapeutic approaches beyond traditional dopamine replacement therapies. […] It is well recognised in human postmortem studies that PD patients have neuronal loss in the substantia nigra par compacta, locus ceruleus and other neuronal populations.

• #4 Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis – Parkinson’s Disease – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536722/

  Parkinsons disease (PD) is a common neurodegenerative disorder. […] The cause of PD is not known, but a number of genetic risk factors have now been characterized, as well as several genes which cause rare familial forms of PD. […] Several processes have been implicated in PD, including mitochondrial dysfunction, defective protein clearance mechanisms, and neuroinflammation, but the way in which these factors interact remains incompletely understood. […] A number of mechanisms have been implicated in PD pathogenesis, with -synuclein aggregation central to the development of the disease. […] Multiple other processes are thought to be involved, with several studies suggesting that abnormal protein clearance, mitochondrial dysfunction, and neuroinflammation play a role in the onset and progression of PD. […] However, the relationship between these pathways remains unclear.

• #5 Parkinson Disease: Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1831191-overview

  Parkinson disease (PD) is one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years and causing progressive disability that can be slowed, but not halted, by treatment. The 2 major neuropathologic findings in Parkinson disease are loss of pigmented dopaminergic neurons of the substantia nigra pars compacta and the presence of Lewy bodies and Lewy neurites. […] Parkinson disease is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years. There are 2 major neuropathologic findings: the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies. […] The loss of dopamine neurons occurs most prominently in the ventral lateral substantia nigra. Approximately 60-80% of dopaminergic neurons are lost before the motor signs of Parkinson disease emerge.

• #6 Parkinson’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Parkinson%27s_disease

  Molecularly, abnormal aggregation of alpha-synuclein is considered a key contributor to PD pathogenesis, although the trigger for this aggregation is debated. Proteostasis disruption and the dysfunction of cell organelles, including endosomes, lysosomes, and mitochondria, are implicated in pathogenesis. Additionally, maladaptive immune and inflammatory responses are potential contributors. The substantial heterogeneity in PD presentation and progression suggests the involvement of multiple interacting triggers and pathogenic pathways. […] Parkinson’s disease has two hallmark pathophysiological processes: the abnormal aggregation of alpha-synuclein that leads to Lewy pathology, and the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The death of these neurons reduces available dopamine in the striatum, which in turn affects circuits controlling movement in the basal ganglia. By the time motor symptoms appear, 50-80 percent of all dopaminergic neurons in the substantia nigra have degenerated.

• #7 Parkinson Disease: Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1831191-overview

  Parkinson disease (PD) is one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years and causing progressive disability that can be slowed, but not halted, by treatment. The 2 major neuropathologic findings in Parkinson disease are loss of pigmented dopaminergic neurons of the substantia nigra pars compacta and the presence of Lewy bodies and Lewy neurites. […] Parkinson disease is recognized as one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years. There are 2 major neuropathologic findings: the loss of pigmented dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies. […] The loss of dopamine neurons occurs most prominently in the ventral lateral substantia nigra. Approximately 60-80% of dopaminergic neurons are lost before the motor signs of Parkinson disease emerge.

• #8 Parkinson’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/symptoms-causes/syc-20376055

  In Parkinson’s disease, nerve cells in the brain called neurons slowly break down or die. Many Parkinson’s disease symptoms are caused by a loss of neurons that produce a chemical messenger in the brain. This messenger is called dopamine. […] Decreased dopamine leads to irregular brain activity. This causes movement problems and other symptoms of Parkinson’s disease. People with Parkinson’s disease also lose a chemical messenger called norepinephrine that controls many body functions, such as blood pressure. […] Many changes happen in the brains of people with Parkinson’s disease. Researchers are studying why the changes happen and the roles they play. These changes include: […] The presence of Lewy bodies. Clumps of proteins in the brain are associated with Parkinson’s disease. These are called Lewy bodies, and researchers believe these proteins hold an important clue to the cause of Parkinson’s disease.

• #9 Parkinson Disease: Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1965354-overview

  Parkinson disease (PD) is one of the most common neurologic disorders, affecting approximately 1% of individuals older than 60 years and causing progressive disability that can be slowed, but not halted, by treatment. The 2 major neuropathologic findings in Parkinson disease are loss of pigmented dopaminergic neurons of the substantia nigra pars compacta and the presence of Lewy bodies and Lewy neurites. […] Parkinson disease is a synucleinopathy. […] The loss of dopamine neurons occurs most prominently in the ventral lateral substantia nigra. Approximately 60-80% of dopaminergic neurons are lost before the motor signs of Parkinson disease emerge. […] Some individuals who were thought to be normal neurologically at the time of their deaths are found to have Lewy bodies on autopsy examination. These incidental Lewy bodies have been hypothesized to represent the presymptomatic phase of Parkinson disease.

• #10 Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-023-01353-3

  The primary pathogenic characteristics of PD include the steady degradation of just a subset of neurons within particular brain areas, such as the SN, as the illness progresses. Dopaminergic neurons are lost exclusively in the ventrolateral SN in the early stages; however, this damage spreads in the late stages. […] Abnormal -synuclein aggregation is one of the most important hypotheses explaining the death of nigrostriatal neurons in PD. […] Oxidative stress (OS) is a major process in aging that directly harms the CNS. […] Mitochondrial dysfunction is increasingly understood to be important in PD pathogenesis. […] Neuroinflammation-related damage in patients with PD. […] The role of gut microbiota in neurological diseases has attracted considerable interest. […] The mechanisms involved in PD are very complex, such as the aggregation of -synuclein, OS, neuroinflammation, ferroptosis, mitochondrial dysfunction, gut dysbiosis, etc.

• #11 Parkinson’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/symptoms-causes/syc-20376055

  In Parkinson’s disease, nerve cells in the brain called neurons slowly break down or die. Many Parkinson’s disease symptoms are caused by a loss of neurons that produce a chemical messenger in the brain. This messenger is called dopamine. […] Decreased dopamine leads to irregular brain activity. This causes movement problems and other symptoms of Parkinson’s disease. People with Parkinson’s disease also lose a chemical messenger called norepinephrine that controls many body functions, such as blood pressure. […] Many changes happen in the brains of people with Parkinson’s disease. Researchers are studying why the changes happen and the roles they play. These changes include: […] The presence of Lewy bodies. Clumps of proteins in the brain are associated with Parkinson’s disease. These are called Lewy bodies, and researchers believe these proteins hold an important clue to the cause of Parkinson’s disease.

• #12 The pathogenesis of Parkinson’s disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/38245249/

  Parkinson’s disease is a progressive neurodegenerative condition associated with the deposition of aggregated -synuclein. Insights into the pathogenesis of Parkinson’s disease have been derived from genetics and molecular pathology. […] Biochemical studies, investigation of transplanted neurons in patients with Parkinson’s disease, and cell and animal model studies suggest that abnormal aggregation of -synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson’s disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson’s disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson’s disease. Although there are currently no disease-modifying treatments for Parkinson’s disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.

• #13 Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis – Parkinson’s Disease – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536722/

  Parkinsons disease (PD) is a common neurodegenerative disorder. […] The cause of PD is not known, but a number of genetic risk factors have now been characterized, as well as several genes which cause rare familial forms of PD. […] Several processes have been implicated in PD, including mitochondrial dysfunction, defective protein clearance mechanisms, and neuroinflammation, but the way in which these factors interact remains incompletely understood. […] A number of mechanisms have been implicated in PD pathogenesis, with -synuclein aggregation central to the development of the disease. […] Multiple other processes are thought to be involved, with several studies suggesting that abnormal protein clearance, mitochondrial dysfunction, and neuroinflammation play a role in the onset and progression of PD. […] However, the relationship between these pathways remains unclear.

• #14 Parkinson’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Parkinson%27s_disease

  Alpha-synuclein is an intracellular protein typically localized to presynaptic terminals and involved in synaptic vesicle trafficking, intracellular transport, and neurotransmitter release. When misfolded, it can aggregate into oligomers and proto-fibrils that in turn lead to Lewy body formation. […] Three major pathways—vesicular trafficking, lysosomal degradation, and mitochondrial maintenance—are known to be affected by and contribute to Parkinson’s pathogenesis, with all three linked to alpha-synuclein. High risk gene variants also impair all three of these processes.

• #15 Parkinson’s disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/symptoms-causes/syc-20376055

  Alpha-synuclein found within Lewy bodies. Alpha-synuclein is a protein found in all Lewy bodies. It occurs in a clumped form that cells can’t break down. This is currently an important focus among Parkinson’s disease researchers. Alpha-synuclein has been found in the spinal fluid of people who later have Parkinson’s disease. […] Altered mitochondria. Mitochondria are powerhouse compartments inside cells that create most of the body’s energy. Changes to mitochondria can cause cell damage. These changes have been found in the brains of people with Parkinson’s disease.

• #16 Current understanding of the molecular mechanisms in Parkinson’s disease: Targets for potential treatments | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-017-0099-z

  Gradual degeneration and loss of dopaminergic neurons in the substantia nigra, pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinsons disease (PD). […] Although the exact mechanism of dopaminergic neuronal loss in SNpc is not well understood. Mitochondrial damage, energy failure, oxidative stress, excitotoxicity, protein misfolding and their aggregation, impairment of protein clearance pathways, cell-autonomous mechanisms and prion-like protein infection may be involved in the onset and progression of PD. […] Among them, protein misfolding and its subsequent accumulation in intracellular spaces has become a leading hypothesis for PD. […] The major misfolded amyloid protein inclusion observed in the intracellular spaces of SNpc neurons in PD is the Lewy bodies (LB), which contain several misfolded amyloid proteins, including alpha-synuclein (SNCA), phosphorylated tau (p-tau), and amyloid beta protein (A).

• #17 Parkinson’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Parkinson%27s_disease

  Molecularly, abnormal aggregation of alpha-synuclein is considered a key contributor to PD pathogenesis, although the trigger for this aggregation is debated. Proteostasis disruption and the dysfunction of cell organelles, including endosomes, lysosomes, and mitochondria, are implicated in pathogenesis. Additionally, maladaptive immune and inflammatory responses are potential contributors. The substantial heterogeneity in PD presentation and progression suggests the involvement of multiple interacting triggers and pathogenic pathways. […] Parkinson’s disease has two hallmark pathophysiological processes: the abnormal aggregation of alpha-synuclein that leads to Lewy pathology, and the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The death of these neurons reduces available dopamine in the striatum, which in turn affects circuits controlling movement in the basal ganglia. By the time motor symptoms appear, 50-80 percent of all dopaminergic neurons in the substantia nigra have degenerated.

• #18 The pathogenesis of Parkinson’s disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/38245249/

  Parkinson’s disease is a progressive neurodegenerative condition associated with the deposition of aggregated -synuclein. Insights into the pathogenesis of Parkinson’s disease have been derived from genetics and molecular pathology. […] Biochemical studies, investigation of transplanted neurons in patients with Parkinson’s disease, and cell and animal model studies suggest that abnormal aggregation of -synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson’s disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson’s disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson’s disease. Although there are currently no disease-modifying treatments for Parkinson’s disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.

• #19 Parkinson Disease: Practice Essentials, Background, Anatomy

  https://emedicine.medscape.com/article/1965354-overview

  The basal ganglia motor circuit modulates the cortical output necessary for normal movement. […] In Parkinson disease, decreased striatal dopamine causes increased inhibitory output from the GPi/SNr via both the direct and indirect pathways. […] The increased inhibition of the thalamocortical pathway suppresses movement. […] Abnormally aggregated alpha-synuclein is the major component of Lewy bodies and Lewy neurites, which are characteristic pathologic findings in Parkinson disease. […] Dysfunction of alpha-synuclein appears to play a central role in the pathogenesis of Parkinson disease, and understanding its relationship to the disease process holds major promise for the development of a cure. […] How the Parkinson disease process begins is not known. Once it is initiated, however, it may propagate by a prionlike process in which misconformed proteins induce the templated misfolding of other protein molecules. […] Preventing the propagation of abnormal alpha-synuclein aggregation may be the key to slowing or stopping Parkinson disease progression.

• #20 Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-023-01353-3

  The primary pathogenic characteristics of PD include the steady degradation of just a subset of neurons within particular brain areas, such as the SN, as the illness progresses. Dopaminergic neurons are lost exclusively in the ventrolateral SN in the early stages; however, this damage spreads in the late stages. […] Abnormal -synuclein aggregation is one of the most important hypotheses explaining the death of nigrostriatal neurons in PD. […] Oxidative stress (OS) is a major process in aging that directly harms the CNS. […] Mitochondrial dysfunction is increasingly understood to be important in PD pathogenesis. […] Neuroinflammation-related damage in patients with PD. […] The role of gut microbiota in neurological diseases has attracted considerable interest. […] The mechanisms involved in PD are very complex, such as the aggregation of -synuclein, OS, neuroinflammation, ferroptosis, mitochondrial dysfunction, gut dysbiosis, etc.

• #21 Common molecular mechanism of Parkinson’s pathology discovered in study | News Center

  https://med.stanford.edu/news/all-news/2016/09/common-molecular-mechanism-of-parkinsons-pathology-discovered.html

  Intracellular defects that lead to cells’ failure to decommission faulty „power packs” known as mitochondria cause nerve cells to die, triggering the symptoms of Parkinson’s disease. […] Stanford University School of Medicine researchers have located an intracellular defect that they believe is probably common to all forms of Parkinson’s disease. […] This defect, which precedes the death of a group of nerve cells whose loss is the hallmark of the condition, play a critical role in triggering that die-off. […] The defect, described in a study published online Sept. 8 in Cell Stem Cell, renders cells unable to quickly dismantle their internal power packs, called mitochondria, when they wear out, stop supplying energy and start spewing out pollutants instead. […] Until now, the question of what causes the death of these dopaminergic nerve cells in Parkinson’s patients has occasioned many highly uncertain guesses backed by little solid evidence.

• #22 Etiology and pathogenesis of Parkinson’s disease: role of mitoch | RRBC

  https://www.dovepress.com/etiology-and-pathogenesis-of-parkinsonrsquos-disease-role-of-mitochond-peer-reviewed-fulltext-article-RRBC

  Neurons critically rely on mitochondrial activity: they are characterized by high energy demand and they are totally dependent on the process of oxidative phosphorylation to produce adenosine triphosphate. Thus, any impairment in mitochondrial function results in neuronal damage and degeneration. Some particular neuronal populations are more susceptible to mitochondrial damage, as it has been recently proposed for the ventral midbrain dopaminergic neurons, the degeneration of which represents a clinical sign of Parkinsons disease. […] Different cellular pathways are involved in the pathogenesis of this neurodegenerative disease, but intriguingly both sporadic and familial forms share common features that essentially recapitulate mitochondrial dysfunction. Mitochondrial biogenesis, bioenergetics, mitochondria dynamics, and quality-control process are the main affected pathways. General consensus agrees on the possibility that deficiency in these processes may represent the cause rather than the consequence of neurodegeneration. […] In this review, we will discuss these aspects and the substantial achievements that have been reached in recent years in identifying specific defects in precise biological processes, eg, mitochondrial quality control.

• #23 Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

  https://www.mdpi.com/1422-0067/23/21/13043

  An increasing number of the population all around the world suffer from age-associated neurodegenerative diseases including Parkinson’s disease (PD). This disorder presents different signs of genetic, epigenetic and environmental origin, and molecular, cellular and intracellular dysfunction. At the molecular level, α-synuclein (αSyn) was identified as the principal molecule constituting the Lewy bodies (LB). The gut microbiota participates in the pathogenesis of PD and may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The most important pathogenetic link is an imbalance of Ca2+ ions, which is associated with redox imbalance in the cells and increased generation of reactive oxygen species (ROS). […] The key features of PD are the accumulation of aggregated αSyn, mitochondrial disorders, neuroinflammation, and the disruption of the blood–brain barrier (BBB) function. All of these factors are involved in damage to dopaminergic neurons. Dysfunction of the mitochondria (MCh) plays a critical role in both sporadic and hereditary forms of PD and is one of the hallmarks of PD. Mitochondrial disorders are among the earliest biochemical signs of the disease and are manifested in disturbances in the interaction of MCh and the endoplasmic reticulum (ER), calcium homeostasis, and an increase in the level of reactive oxygen species (ROS).

• #24 Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

  https://www.mdpi.com/1422-0067/23/21/13043

  In the pathogenesis of PD, there are several kinds of disturbances in bioenergetics in the cells of the nigrostriatal system: a decrease in the activity of complex I of the mitochondrial respiratory chain, an increase in the production of ROS by MCh, the ROS-mediated damage to mitochondrial DNA and of other molecules, disturbed mitophagy, followed by various functional disorders of MCh and their host cells. Elevated levels of ROS and energy deficit disrupt the interactions between MCh and ER, reduce the function of lysosomes, and disrupt calcium homeostasis. […] The molecular pathogenesis of sporadic forms includes not only oxidative stress, but also many other pathways and mechanisms: mitochondrial dysfunction, αSyn proteostasis, calcium homeostasis, axonal transport, and neuroinflammation. Mitochondrial dysfunction plays a fundamental and complex role in many neurodegenerative disorders, including PD. PD-associated mitochondrial dysfunction can result from a number of causes, including impairment of mitochondrial biogenesis, increased ROS production, defective mitophagy, compromised trafficking, electron transport chain (ETC) dysfunction, variations to mitochondrial dynamics, calcium imbalance and possibly other indirect influences on mitochondrial function from unrelated pathways.

• #25 Parkinson’s disease: etiopathogenesis and treatment | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/91/8/795

  Several key molecular events and hallmarks have been consistently reported in human postmortem tissues, in vitro human cells lines, human brain organoids and animal models. These include -synuclein misfolding and aggregation, mitochondrial dysfunction, impairment of protein clearance (involving key ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress. […] Abnormal aggregation of the protein has been found to be toxic to dopaminergic neurons leading to neurodegeneration associated with PD. […] Reduction of mitochondrial complex 1 activity has been found in PD patients and the use of its inhibitor (eg, rotenone) has been found to produce mitochondrial damage in experimental PD models. […] Both innate and adaptive immune response abnormalities have been highlighted in PD patients, including increase in proinflammatory cytokines and altered immune cell population. […] There is growing body of evidence of gut-brain link as a contributory factor in PD pathogenesis where vagus nerves acts as a highway for aggregated -synuclein to transmit from the gastrointestinal tract to the lower brainstem.

• #26 A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson’s disease with insights into screening models | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-023-01047-4

  The earliest symptoms of PD are mitochondrial dysfunction and mitophagy. […] Reactive oxygen species in PD such as hydroxyl radical (OH), superoxide anion (O2), and hydrogen peroxide (H2O2) are synthesized because within the mitochondria there is physiological metabolism of molecular oxygen. […] An increase in ROS production in PD has shown failure in mitochondrial complex I, according to studies utilizing the paraquat and MPTP-like toxins, which are known to cause PD-like symptoms including dopaminergic neuronal cells to die and protein clusters are produced. […] The precise role of alpha-synuclein, however, is unknown; it is difficult to determine its relationship to PD. […] The complexity of this PD is becoming more apparent, so we must first comprehend how these animal models function.

• #27 Promising Parkinson’s drug decoded

  https://medicalxpress.com/news/2025-05-parkinson-drug-decoded.html

  Inhibition of the deubiquitinase USP30 promotes mitophagy and thus mitochondrial renewal in dopaminergic nerve cells and could therefore form the basis for an innovative therapy for Parkinson’s disease. […] Impaired quality control of mitochondria plays a central role in Parkinson’s disease. […] The exact cause of nerve cell death remains unclear. However, there are indications that defects in their mitochondria could be responsible. Nerve cells in particular are highly dependent on these organelles, as they require high amounts of energy. […] An important enzyme in mitophagy is the deubiquitinase (DUB) USP30. It removes ubiquitin marks from defective mitochondria that are destined for degradation. […] An inhibitor of this enzyme, which could promote mitophagy and thus improve nerve function, is currently being investigated in clinical trials: It is considered a promising candidate drug for the treatment of Parkinson’s disease and chronic kidney disease.

• #28

  https://link.springer.com/article/10.1007/s10863-019-09798-4

  DJ-1 protein has multiple specific mechanisms to protect dopaminergic neurons against neurodegeneration in Parkinson’s disease. […] DJ-1 is shown to be a co-activator of the transcription factor NF-kB. […] The ability of the DJ-1 to induce activation of different transcriptional factors and change redox balance protect neurons against aggregation of -synuclein and oligomer-induced neurodegeneration. […] DJ-1 plays a role of oxidative stress sensor – it eliminates peroxide by autoxidation. […] DJ-1 participates in a number of signaling pathways, including control of mitochondrial quality and reaction to oxidative stress. […] DJ-1 protects dopaminergic neurons against oxidative damage not only in vitro, but also in vivo. […] Oxidised DJ-1 was shown to be significantly decreased in idiopathic PD brain, suggesting altered complex function controlled by DJ-1 may also play a role in the more common sporadic form of the disease.

• #29 Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-023-01353-3

  The primary pathogenic characteristics of PD include the steady degradation of just a subset of neurons within particular brain areas, such as the SN, as the illness progresses. Dopaminergic neurons are lost exclusively in the ventrolateral SN in the early stages; however, this damage spreads in the late stages. […] Abnormal -synuclein aggregation is one of the most important hypotheses explaining the death of nigrostriatal neurons in PD. […] Oxidative stress (OS) is a major process in aging that directly harms the CNS. […] Mitochondrial dysfunction is increasingly understood to be important in PD pathogenesis. […] Neuroinflammation-related damage in patients with PD. […] The role of gut microbiota in neurological diseases has attracted considerable interest. […] The mechanisms involved in PD are very complex, such as the aggregation of -synuclein, OS, neuroinflammation, ferroptosis, mitochondrial dysfunction, gut dysbiosis, etc.

• #30 Pathogenesis of parkinson’s disease: dopamine, vesicles and α-synuclein | Nature Reviews Neuroscience

  https://www.nature.com/articles/nrn983

  Parkinson’s disease is a progressive neurological disorder characterized primarily by motor symptoms that include rigidity, hypokinesia and tremor. The most pronounced neuropathological feature is a loss of dopaminergic neurons in the substantia nigra pars compacta, which leads to a reduction in dopamine levels in the target region, the striatum. In the substantia nigra, some neurons have intracytoplasmic inclusions known as Lewy bodies. […] In most patients, Parkinson’s disease shows no clear inheritance and the cause of neurodegeneration is not known. Several disease mechanisms have been proposed, including oxidative stress and mitochondrial dysfunction. Some emphasis has been placed on the possibility that environmental toxins trigger these pathological changes. […] We speculate why changes in these diverse genes lead to a neurodegenerative process that is relatively focused on dopamine-containing neurons, and emphasize the role of dopamine-dependent oxidative stress in this process. We believe that there are multiple aetiological triggers, resulting from either genetic changes or environmental insults, which share the same final common pathway to cell death in dopaminergic neurons. Increased levels of cytoplasmic dopamine in nigral neurons in Parkinson’s disease patients might result in dopamine oxidation and the generation of reactive oxygen species that can damage and eventually kill these neurons.

• #31 Role of dopamine in the pathophysiology of Parkinson’s disease | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-023-00378-6

  A pathological feature of Parkinsons disease (PD) is the progressive loss of dopaminergic neurons and decreased dopamine (DA) content in the substantia nigra pars compacta in PD brains. […] Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology. […] Disturbances of DA synthesis, storage, transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models. […] The exact PD pathogenesis remains to be clarified. However, evidence shows that oxidation of endogenous DA can induce specific oxidative stress in dopaminergic neurons. […] DA oxidation can occur spontaneously or be mediated by enzymes or metal ions, producing deleterious DA oxidative by-products. […] Many reactive DA metabolites are toxic to dopaminergic neurons, including reactive oxygen species (ROS), DA quinones (DAQs) and 3,4-dihydroxyphenylacetaldehyde (DOPAL).

• #32 Role of dopamine in the pathophysiology of Parkinson’s disease | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-023-00378-6

  A pathological feature of Parkinsons disease (PD) is the progressive loss of dopaminergic neurons and decreased dopamine (DA) content in the substantia nigra pars compacta in PD brains. […] Accumulating evidence suggests that DA interacts with environmental and genetic factors to contribute to PD pathophysiology. […] Disturbances of DA synthesis, storage, transportation and metabolism have been shown to promote neurodegeneration of dopaminergic neurons in various PD models. […] The exact PD pathogenesis remains to be clarified. However, evidence shows that oxidation of endogenous DA can induce specific oxidative stress in dopaminergic neurons. […] DA oxidation can occur spontaneously or be mediated by enzymes or metal ions, producing deleterious DA oxidative by-products. […] Many reactive DA metabolites are toxic to dopaminergic neurons, including reactive oxygen species (ROS), DA quinones (DAQs) and 3,4-dihydroxyphenylacetaldehyde (DOPAL).

• #33 Role of dopamine in the pathophysiology of Parkinson’s disease | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-023-00378-6

  DA impairs the functions of mitochondria, ubiquitinproteasome system (UPS), lysosome and autophagy, resulting in DA neuron vulnerability. […] DA and its derivatives are involved in the toxicity of PD-related neurotoxins, such as rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron species. […] DA is also involved in the PD pathogenesis associated with genetic factors, including SNCA (encoding -synuclein [-syn]), LRRK2 (leucine-rich repeat kinase 2), PINK1 (PTEN-induced kinase 1), Parkin, DJ-1 and GBA1 (glucocerebrosidase-1 [GCase]), contributing to DA neuronal degeneration. […] DA-relevant toxicity in PD pathogenesis has been demonstrated in multiple in vitro and in vivo PD models. […] Direct injection of DA (up to 1 mol) into the rat striatum led to the loss of dopaminergic nerve terminals and the formation of cysteinyl adducts of DA in a DA-dose-dependent manner.

• #34 A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson’s disease with insights into screening models | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-023-01047-4

  The earliest symptoms of PD are mitochondrial dysfunction and mitophagy. […] Reactive oxygen species in PD such as hydroxyl radical (OH), superoxide anion (O2), and hydrogen peroxide (H2O2) are synthesized because within the mitochondria there is physiological metabolism of molecular oxygen. […] An increase in ROS production in PD has shown failure in mitochondrial complex I, according to studies utilizing the paraquat and MPTP-like toxins, which are known to cause PD-like symptoms including dopaminergic neuronal cells to die and protein clusters are produced. […] The precise role of alpha-synuclein, however, is unknown; it is difficult to determine its relationship to PD. […] The complexity of this PD is becoming more apparent, so we must first comprehend how these animal models function.

• #35 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Parkinsons-Disease-Pathophysiology.aspx

  Certain genes have been found that may be associated with Parkinsons disease. […] Alpha-synculein is the main component of Lewy bodies, which are found in cells of all patients with Parkinson’s disease. In patients with a mutated gene for alpha synculein an altered protein product is formed. This protein accumulates in the cell and attracts other proteins in order to form a deposit which leads to the damage of the neuron. […] These are unstable molecules produced during normal chemical reactions in the body. When they interact with other molecules they have the ability to damage tissues like neurons. […] With age there is a normal decline of the dopamine producing neurons, which leads to the premature loss of dopamine. […] Several toxins like illegal drugs contaminated with a chemical called MPTP may cause severe Parkinson-like symptoms. It was found that once MPTP crossed into the brain it started killing brain cells. […] Other toxins and exposures associated with Parkinsons disease include: manganese dust, carbon disulphide, severe carbon monoxide (CO) poisoning, the insecticides permethrin and beta-hexachlorocyclohexane (beta-HCH), the herbicides paraquat and 2,4-dichlorophenoxyacetic acid and the fungicide maneb.

• #36 Role of dopamine in the pathophysiology of Parkinson’s disease | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-023-00378-6

  Injection of AM, a cyclized DAQ, into the SN of rats induced dopaminergic neuronal degeneration and motor impairment. […] Injection of DOPAL into the rat SN region resulted in DA neuronal loss. […] Furthermore, deregulation of endogenous DA synthesis, storage, transportation and metabolism by pharmacological and genetic approaches can lead to deleterious effects on dopaminergic neurons. […] DA exerts toxicity via its deleterious metabolic by-products, including reactive ROS, DAQs and DOPAL. […] The DA-derived DAQs can irreversibly conjugate to the sulfhydryl groups of cysteine residues via Michael-addition (MA) reaction, leading to protein misfolding and loss of function. […] DAQs can irreversibly inhibit the activities of proteasomes, whereas small-molecule ROS only induce reversible proteasome inhibition.

• #37 Role of dopamine in the pathophysiology of Parkinson’s disease | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-023-00378-6

  The enhanced mitochondrial oxidative stress leads to DA oxidation with generation of DAQs, conjugation of DAQs with GBA1, inhibition of GBA1 enzymatic activity, lysosomal dysfunction, and accumulation of deleterious -syn protein. […] DOPAL is also reactive and can be an endogenous neurotoxin due to the presence of its both aldehyde and catechol moieties. […] The neurotoxicity of DOPAL has been reported in various studies both in vitro and in vivo. […] DOPAL can conjugate through its aldehyde moiety with lysine residues of proteins via the SB reaction. […] The conjugation of DOPAL to lysine residues interferes with many cellular events and down-regulates cell viability, as evidenced by ubiquitin oligomerization, accumulation of ubiquitinated proteins and impairment of UPS functions upon DOPAL challenges.

• #38 Parkinson’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Parkinson%27s_disease

  Molecularly, abnormal aggregation of alpha-synuclein is considered a key contributor to PD pathogenesis, although the trigger for this aggregation is debated. Proteostasis disruption and the dysfunction of cell organelles, including endosomes, lysosomes, and mitochondria, are implicated in pathogenesis. Additionally, maladaptive immune and inflammatory responses are potential contributors. The substantial heterogeneity in PD presentation and progression suggests the involvement of multiple interacting triggers and pathogenic pathways. […] Parkinson’s disease has two hallmark pathophysiological processes: the abnormal aggregation of alpha-synuclein that leads to Lewy pathology, and the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The death of these neurons reduces available dopamine in the striatum, which in turn affects circuits controlling movement in the basal ganglia. By the time motor symptoms appear, 50-80 percent of all dopaminergic neurons in the substantia nigra have degenerated.

• #39 Parkinson’s disease: etiopathogenesis and treatment | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/91/8/795

  Several key molecular events and hallmarks have been consistently reported in human postmortem tissues, in vitro human cells lines, human brain organoids and animal models. These include -synuclein misfolding and aggregation, mitochondrial dysfunction, impairment of protein clearance (involving key ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress. […] Abnormal aggregation of the protein has been found to be toxic to dopaminergic neurons leading to neurodegeneration associated with PD. […] Reduction of mitochondrial complex 1 activity has been found in PD patients and the use of its inhibitor (eg, rotenone) has been found to produce mitochondrial damage in experimental PD models. […] Both innate and adaptive immune response abnormalities have been highlighted in PD patients, including increase in proinflammatory cytokines and altered immune cell population. […] There is growing body of evidence of gut-brain link as a contributory factor in PD pathogenesis where vagus nerves acts as a highway for aggregated -synuclein to transmit from the gastrointestinal tract to the lower brainstem.

• #40 Parkinson’s disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/parkinsons-disease/

  Some gene variants appear to disturb the cell machinery that breaks down (degrades) unwanted proteins in dopamine-producing neurons. As a result, undegraded proteins accumulate, leading to the impairment or death of these cells. Other variants may affect the function of mitochondria, the energy-producing structures within cells. As a byproduct of energy production, mitochondria make unstable molecules called free radicals that can damage cells. Cells normally counteract the effects of free radicals before they cause damage, but variants can disrupt this process. As a result, free radicals may accumulate and impair or kill dopamine-producing neurons. […] In most cases of Parkinson’s disease, protein deposits called Lewy bodies appear in dead or dying dopamine-producing neurons. (When Lewy bodies are not present, the condition is sometimes referred to as parkinsonism.) It is unclear whether Lewy bodies play a role in killing nerve cells or if they are part of the cells’ response to the disease.

• #41 Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis – Parkinson’s Disease – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536722/

  Parkinsons disease (PD) is a common neurodegenerative disorder. […] The cause of PD is not known, but a number of genetic risk factors have now been characterized, as well as several genes which cause rare familial forms of PD. […] Several processes have been implicated in PD, including mitochondrial dysfunction, defective protein clearance mechanisms, and neuroinflammation, but the way in which these factors interact remains incompletely understood. […] A number of mechanisms have been implicated in PD pathogenesis, with -synuclein aggregation central to the development of the disease. […] Multiple other processes are thought to be involved, with several studies suggesting that abnormal protein clearance, mitochondrial dysfunction, and neuroinflammation play a role in the onset and progression of PD. […] However, the relationship between these pathways remains unclear.

• #42 Current understanding of the molecular mechanisms in Parkinson’s disease: Targets for potential treatments | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-017-0099-z

  PD is a multifactorial disease, where both genetic and non-genetic, such as environmental factors, are involved. The most salient mechanisms involved in the development of PD include the accumulation of misfolded proteins aggregates, failure of protein clearance pathways, mitochondrial damage, oxidative stress, excitotoxicity, neuroinflammation, and genetic mutations. […] One of the hallmark pathologies of PD is the intracellular accumulation of LB in DA neurons of the SNpc, which contain misfolded aggregates of SNCA and other associated proteins. […] The oligomers, proto-fibrils, and fibrils of SNCA or other misfolded amyloid proteins can make a pore in the membrane, causing neuronal death via oxidative stress, energy failure, excitotoxicity, and neuroinflammation. […] The p-tau can also be co-localized with LB, which is often associated with the development of sporadic PD. […] Although NFTs are associated most closely with AD, they can co-localize with SNCA in LB and play an important role in destabilization of DA-neuronal architecture, which ultimately leads to rapid degeneration and death of DA neurons.

• #43 Role of dopamine in the pathophysiology of Parkinson’s disease | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-023-00378-6

  DA impairs the functions of mitochondria, ubiquitinproteasome system (UPS), lysosome and autophagy, resulting in DA neuron vulnerability. […] DA and its derivatives are involved in the toxicity of PD-related neurotoxins, such as rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron species. […] DA is also involved in the PD pathogenesis associated with genetic factors, including SNCA (encoding -synuclein [-syn]), LRRK2 (leucine-rich repeat kinase 2), PINK1 (PTEN-induced kinase 1), Parkin, DJ-1 and GBA1 (glucocerebrosidase-1 [GCase]), contributing to DA neuronal degeneration. […] DA-relevant toxicity in PD pathogenesis has been demonstrated in multiple in vitro and in vivo PD models. […] Direct injection of DA (up to 1 mol) into the rat striatum led to the loss of dopaminergic nerve terminals and the formation of cysteinyl adducts of DA in a DA-dose-dependent manner.

• #44 The pathogenesis of Parkinson’s disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/38245249/

  Parkinson’s disease is a progressive neurodegenerative condition associated with the deposition of aggregated -synuclein. Insights into the pathogenesis of Parkinson’s disease have been derived from genetics and molecular pathology. […] Biochemical studies, investigation of transplanted neurons in patients with Parkinson’s disease, and cell and animal model studies suggest that abnormal aggregation of -synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson’s disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson’s disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson’s disease. Although there are currently no disease-modifying treatments for Parkinson’s disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.

• #45 A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson’s disease with insights into screening models | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-023-01047-4

  Microglia and astrocytes can cause neuroinflammation, which can speed the course of pathogenic damage to substantia nigra (SN). The mechanism of Parkinson’s disease (PD) that causes tremors, rigidity, and bradykinesia is a decrease in striatal dopamine. […] The most well-known neurotoxin is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which destroys dopaminergic neurons, resulting in the development of Parkinson’s disease (PD). […] Dopamine auto-oxidation in dopaminergic (DA) neurons is a significant source of reactive oxygen species (ROS) that causes neuronal oxidative stress. […] Most common genes which when affected by mutation lead to development and progression of Parkinson’s disease (PD) are LRRK2, SNCA (alpha-synuclein protein), DJ-1, PRKN (Parkin protein), PINK1, GBA1, and VPS35.

• #46 Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-023-01353-3

  The primary pathogenic characteristics of PD include the steady degradation of just a subset of neurons within particular brain areas, such as the SN, as the illness progresses. Dopaminergic neurons are lost exclusively in the ventrolateral SN in the early stages; however, this damage spreads in the late stages. […] Abnormal -synuclein aggregation is one of the most important hypotheses explaining the death of nigrostriatal neurons in PD. […] Oxidative stress (OS) is a major process in aging that directly harms the CNS. […] Mitochondrial dysfunction is increasingly understood to be important in PD pathogenesis. […] Neuroinflammation-related damage in patients with PD. […] The role of gut microbiota in neurological diseases has attracted considerable interest. […] The mechanisms involved in PD are very complex, such as the aggregation of -synuclein, OS, neuroinflammation, ferroptosis, mitochondrial dysfunction, gut dysbiosis, etc.

• #47 Parkinson’s disease: etiopathogenesis and treatment | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/91/8/795

  Several key molecular events and hallmarks have been consistently reported in human postmortem tissues, in vitro human cells lines, human brain organoids and animal models. These include -synuclein misfolding and aggregation, mitochondrial dysfunction, impairment of protein clearance (involving key ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress. […] Abnormal aggregation of the protein has been found to be toxic to dopaminergic neurons leading to neurodegeneration associated with PD. […] Reduction of mitochondrial complex 1 activity has been found in PD patients and the use of its inhibitor (eg, rotenone) has been found to produce mitochondrial damage in experimental PD models. […] Both innate and adaptive immune response abnormalities have been highlighted in PD patients, including increase in proinflammatory cytokines and altered immune cell population. […] There is growing body of evidence of gut-brain link as a contributory factor in PD pathogenesis where vagus nerves acts as a highway for aggregated -synuclein to transmit from the gastrointestinal tract to the lower brainstem.

• #48 A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson’s disease with insights into screening models | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-023-01047-4

  Microglia and astrocytes can cause neuroinflammation, which can speed the course of pathogenic damage to substantia nigra (SN). The mechanism of Parkinson’s disease (PD) that causes tremors, rigidity, and bradykinesia is a decrease in striatal dopamine. […] The most well-known neurotoxin is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which destroys dopaminergic neurons, resulting in the development of Parkinson’s disease (PD). […] Dopamine auto-oxidation in dopaminergic (DA) neurons is a significant source of reactive oxygen species (ROS) that causes neuronal oxidative stress. […] Most common genes which when affected by mutation lead to development and progression of Parkinson’s disease (PD) are LRRK2, SNCA (alpha-synuclein protein), DJ-1, PRKN (Parkin protein), PINK1, GBA1, and VPS35.

• #49 NEUROINFLAMMATION AND IMMUNE DYSFUNCTION IN THE PATHOGENESIS OF PARKINSON’S DISEASE – Idova – Zhurnal Vysshei Nervnoi Deyatelnosti Imeni I.P. Pavlova

  https://journals.eco-vector.com/0044-4677/article/view/652022

  Parkinsons disease (PD) is a chronic progressive neurodegenerative disorder, characterized by dopaminergic neuronal loss, aggregation of alpha-synuclein and severe motor impairments. This review summarizes current data on the key role of neuroinflammation and immune dysfunction in neurodegeneration and disease development. […] We examine clinical and experimental evidence for microglia activation, participation of Toll-like receptors in this process, a wide range of chemokines and pro- and anti-inflammatory cytokines in the course of the disease. Emphasis is also made on the impact of the innate and adaptive immune responses in the mechanisms of systemic inflammation both in the brain and in the periphery. […] The involvement of brain-infiltrating immune cells and their subpopulations in the process of neuroinflammation and neurodegeneration, changes in the composition and phenotype of peripheral immune cells and their functional characteristics are discussed. […] Analysis of immune cell subsets and their ratios reveals subtle PD-specific changes in cellular populations that can be used as reliable biomarkers for diagnosis, prognosis of the disease course, and development of new approaches for anti-inflammatory and targeted therapies in PD.

• #50 The pathogenesis of Parkinson’s disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/38245249/

  Parkinson’s disease is a progressive neurodegenerative condition associated with the deposition of aggregated -synuclein. Insights into the pathogenesis of Parkinson’s disease have been derived from genetics and molecular pathology. […] Biochemical studies, investigation of transplanted neurons in patients with Parkinson’s disease, and cell and animal model studies suggest that abnormal aggregation of -synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson’s disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson’s disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson’s disease. Although there are currently no disease-modifying treatments for Parkinson’s disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.

• #51 NEUROINFLAMMATION AND IMMUNE DYSFUNCTION IN THE PATHOGENESIS OF PARKINSON’S DISEASE – Idova – Zhurnal Vysshei Nervnoi Deyatelnosti Imeni I.P. Pavlova

  https://journals.eco-vector.com/0044-4677/article/view/652022

  Parkinsons disease (PD) is a chronic progressive neurodegenerative disorder, characterized by dopaminergic neuronal loss, aggregation of alpha-synuclein and severe motor impairments. This review summarizes current data on the key role of neuroinflammation and immune dysfunction in neurodegeneration and disease development. […] We examine clinical and experimental evidence for microglia activation, participation of Toll-like receptors in this process, a wide range of chemokines and pro- and anti-inflammatory cytokines in the course of the disease. Emphasis is also made on the impact of the innate and adaptive immune responses in the mechanisms of systemic inflammation both in the brain and in the periphery. […] The involvement of brain-infiltrating immune cells and their subpopulations in the process of neuroinflammation and neurodegeneration, changes in the composition and phenotype of peripheral immune cells and their functional characteristics are discussed. […] Analysis of immune cell subsets and their ratios reveals subtle PD-specific changes in cellular populations that can be used as reliable biomarkers for diagnosis, prognosis of the disease course, and development of new approaches for anti-inflammatory and targeted therapies in PD.

• #52 Parkinson’s disease: etiopathogenesis and treatment | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/91/8/795

  Several key molecular events and hallmarks have been consistently reported in human postmortem tissues, in vitro human cells lines, human brain organoids and animal models. These include -synuclein misfolding and aggregation, mitochondrial dysfunction, impairment of protein clearance (involving key ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress. […] Abnormal aggregation of the protein has been found to be toxic to dopaminergic neurons leading to neurodegeneration associated with PD. […] Reduction of mitochondrial complex 1 activity has been found in PD patients and the use of its inhibitor (eg, rotenone) has been found to produce mitochondrial damage in experimental PD models. […] Both innate and adaptive immune response abnormalities have been highlighted in PD patients, including increase in proinflammatory cytokines and altered immune cell population. […] There is growing body of evidence of gut-brain link as a contributory factor in PD pathogenesis where vagus nerves acts as a highway for aggregated -synuclein to transmit from the gastrointestinal tract to the lower brainstem.

• #53 The pathogenesis of Parkinson’s disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/38245249/

  Parkinson’s disease is a progressive neurodegenerative condition associated with the deposition of aggregated -synuclein. Insights into the pathogenesis of Parkinson’s disease have been derived from genetics and molecular pathology. […] Biochemical studies, investigation of transplanted neurons in patients with Parkinson’s disease, and cell and animal model studies suggest that abnormal aggregation of -synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson’s disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson’s disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson’s disease. Although there are currently no disease-modifying treatments for Parkinson’s disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.

• #54 Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

  https://www.mdpi.com/1422-0067/23/21/13043

  An increasing number of the population all around the world suffer from age-associated neurodegenerative diseases including Parkinson’s disease (PD). This disorder presents different signs of genetic, epigenetic and environmental origin, and molecular, cellular and intracellular dysfunction. At the molecular level, α-synuclein (αSyn) was identified as the principal molecule constituting the Lewy bodies (LB). The gut microbiota participates in the pathogenesis of PD and may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The most important pathogenetic link is an imbalance of Ca2+ ions, which is associated with redox imbalance in the cells and increased generation of reactive oxygen species (ROS). […] The key features of PD are the accumulation of aggregated αSyn, mitochondrial disorders, neuroinflammation, and the disruption of the blood–brain barrier (BBB) function. All of these factors are involved in damage to dopaminergic neurons. Dysfunction of the mitochondria (MCh) plays a critical role in both sporadic and hereditary forms of PD and is one of the hallmarks of PD. Mitochondrial disorders are among the earliest biochemical signs of the disease and are manifested in disturbances in the interaction of MCh and the endoplasmic reticulum (ER), calcium homeostasis, and an increase in the level of reactive oxygen species (ROS).

• #55 Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-023-01353-3

  The primary pathogenic characteristics of PD include the steady degradation of just a subset of neurons within particular brain areas, such as the SN, as the illness progresses. Dopaminergic neurons are lost exclusively in the ventrolateral SN in the early stages; however, this damage spreads in the late stages. […] Abnormal -synuclein aggregation is one of the most important hypotheses explaining the death of nigrostriatal neurons in PD. […] Oxidative stress (OS) is a major process in aging that directly harms the CNS. […] Mitochondrial dysfunction is increasingly understood to be important in PD pathogenesis. […] Neuroinflammation-related damage in patients with PD. […] The role of gut microbiota in neurological diseases has attracted considerable interest. […] The mechanisms involved in PD are very complex, such as the aggregation of -synuclein, OS, neuroinflammation, ferroptosis, mitochondrial dysfunction, gut dysbiosis, etc.

• #56 New study puts gut microbiome at the center of Parkinson’s disease pathogenesis – UAB News

  https://www.uab.edu/news/research-innovation/new-study-puts-gut-microbiome-at-the-center-of-parkinson-s-disease-pathogenesis

  New research from the University of Alabama at Birmingham says the gut microbiome is involved in multiple pathways in the pathogenesis of Parkinsons disease. The findings, published in Nature Communications, show a wide imbalance in microbiome composition in persons with Parkinsons disease. […] The study reports Parkinsons disease metagenome is indicative of a disease-promoting microbiome. […] We found evidence for multiple mechanisms that we know are linked to PD, but we didn’t know they were happening in the gut also and are orchestrated by the microbiome, Payami said. […] Investigators found an overabundance of opportunistic pathogens and immunogenic components, which suggest infection and inflammation at play, overproduction of toxic molecules, and overabundance of the bacterial product curli. This induces PD pathology and dysregulation of neurotransmitters, including L-dopa. At the same time, there was a shortage of neuroprotective molecules and anti-inflammatory components, which makes recovery difficult.

• #57 The pathogenesis of Parkinson’s disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/38245249/

  Parkinson’s disease is a progressive neurodegenerative condition associated with the deposition of aggregated -synuclein. Insights into the pathogenesis of Parkinson’s disease have been derived from genetics and molecular pathology. […] Biochemical studies, investigation of transplanted neurons in patients with Parkinson’s disease, and cell and animal model studies suggest that abnormal aggregation of -synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson’s disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson’s disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson’s disease. Although there are currently no disease-modifying treatments for Parkinson’s disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.

• #58 New study puts gut microbiome at the center of Parkinson’s disease pathogenesis – UAB News

  https://www.uab.edu/news/research-innovation/new-study-puts-gut-microbiome-at-the-center-of-parkinson-s-disease-pathogenesis

  New research from the University of Alabama at Birmingham says the gut microbiome is involved in multiple pathways in the pathogenesis of Parkinsons disease. The findings, published in Nature Communications, show a wide imbalance in microbiome composition in persons with Parkinsons disease. […] The study reports Parkinsons disease metagenome is indicative of a disease-promoting microbiome. […] We found evidence for multiple mechanisms that we know are linked to PD, but we didn’t know they were happening in the gut also and are orchestrated by the microbiome, Payami said. […] Investigators found an overabundance of opportunistic pathogens and immunogenic components, which suggest infection and inflammation at play, overproduction of toxic molecules, and overabundance of the bacterial product curli. This induces PD pathology and dysregulation of neurotransmitters, including L-dopa. At the same time, there was a shortage of neuroprotective molecules and anti-inflammatory components, which makes recovery difficult.

• #59 New study puts gut microbiome at the center of Parkinson’s disease pathogenesis – UAB News

  https://www.uab.edu/news/research-innovation/new-study-puts-gut-microbiome-at-the-center-of-parkinson-s-disease-pathogenesis

  The study, utilizing the relatively new field of metagenomics, demonstrated an imbalance in the gut microbiome of patients with Parkinsons disease. […] We have shown that there is a widespread imbalance in the Parkinsons metagenome, creating an environment that is permissive for neurodegenerative events and is prohibitive of recovery. […] Parkinsons disease is a progressively debilitating disorder that affected 4 million individuals in the year 2005 and is projected to double to 8.7 million individuals by the year 2030. Although historically defined as a movement disorder, PD is a multi-systemic disease. It is speculated that PD is caused by various combinations of genetic susceptibility and environmental triggers, although no causative combination has yet been identified. The connection between PD and the gastrointestinal system has long been established.

• #60 New study puts gut microbiome at the center of Parkinson’s disease pathogenesis – UAB News

  https://www.uab.edu/news/research-innovation/new-study-puts-gut-microbiome-at-the-center-of-parkinson-s-disease-pathogenesis

  New research from the University of Alabama at Birmingham says the gut microbiome is involved in multiple pathways in the pathogenesis of Parkinsons disease. The findings, published in Nature Communications, show a wide imbalance in microbiome composition in persons with Parkinsons disease. […] The study reports Parkinsons disease metagenome is indicative of a disease-promoting microbiome. […] We found evidence for multiple mechanisms that we know are linked to PD, but we didn’t know they were happening in the gut also and are orchestrated by the microbiome, Payami said. […] Investigators found an overabundance of opportunistic pathogens and immunogenic components, which suggest infection and inflammation at play, overproduction of toxic molecules, and overabundance of the bacterial product curli. This induces PD pathology and dysregulation of neurotransmitters, including L-dopa. At the same time, there was a shortage of neuroprotective molecules and anti-inflammatory components, which makes recovery difficult.

• #61 Parkinson’s disease: etiopathogenesis and treatment | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/91/8/795

  Several key molecular events and hallmarks have been consistently reported in human postmortem tissues, in vitro human cells lines, human brain organoids and animal models. These include -synuclein misfolding and aggregation, mitochondrial dysfunction, impairment of protein clearance (involving key ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress. […] Abnormal aggregation of the protein has been found to be toxic to dopaminergic neurons leading to neurodegeneration associated with PD. […] Reduction of mitochondrial complex 1 activity has been found in PD patients and the use of its inhibitor (eg, rotenone) has been found to produce mitochondrial damage in experimental PD models. […] Both innate and adaptive immune response abnormalities have been highlighted in PD patients, including increase in proinflammatory cytokines and altered immune cell population. […] There is growing body of evidence of gut-brain link as a contributory factor in PD pathogenesis where vagus nerves acts as a highway for aggregated -synuclein to transmit from the gastrointestinal tract to the lower brainstem.

• #62 Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

  https://www.mdpi.com/1422-0067/23/21/13043

  Most cases of sporadic PD are characterized by abnormal accumulation and aggregation of αSyn within neuronal cells in the nigrostriatum, which is converted into amyloid fibrils and deposited in LB. […] A study of the intestinal nervous system has shown that disturbances in intestinal permeability and systemic exposure to bacterial antigens induce the expression of inflammatory cytokines, such as tumor necrosis factor (TNF-α) or interleukin (IL)-1β and IL-6, which disrupt the integrity of the BBB, contribute to the accumulation of αSyn in SN and lead to the death of dopaminergic neurons.

• #63 Parkinson’s disease: etiopathogenesis and treatment | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/91/8/795

  Several key molecular events and hallmarks have been consistently reported in human postmortem tissues, in vitro human cells lines, human brain organoids and animal models. These include -synuclein misfolding and aggregation, mitochondrial dysfunction, impairment of protein clearance (involving key ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress. […] Abnormal aggregation of the protein has been found to be toxic to dopaminergic neurons leading to neurodegeneration associated with PD. […] Reduction of mitochondrial complex 1 activity has been found in PD patients and the use of its inhibitor (eg, rotenone) has been found to produce mitochondrial damage in experimental PD models. […] Both innate and adaptive immune response abnormalities have been highlighted in PD patients, including increase in proinflammatory cytokines and altered immune cell population. […] There is growing body of evidence of gut-brain link as a contributory factor in PD pathogenesis where vagus nerves acts as a highway for aggregated -synuclein to transmit from the gastrointestinal tract to the lower brainstem.

• #64 Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

  https://www.mdpi.com/1422-0067/23/21/13043

  Most cases of sporadic PD are characterized by abnormal accumulation and aggregation of αSyn within neuronal cells in the nigrostriatum, which is converted into amyloid fibrils and deposited in LB. […] A study of the intestinal nervous system has shown that disturbances in intestinal permeability and systemic exposure to bacterial antigens induce the expression of inflammatory cytokines, such as tumor necrosis factor (TNF-α) or interleukin (IL)-1β and IL-6, which disrupt the integrity of the BBB, contribute to the accumulation of αSyn in SN and lead to the death of dopaminergic neurons.

• #65 Parkinson’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Parkinson%27s_disease

  Most Parkinson’s disease cases are sporadic, though contributing factors have been identified. Pathophysiology involves progressive degeneration of nerve cells in the substantia nigra, a midbrain region that provides dopamine to the basal ganglia, a system involved in voluntary motor control. The cause of this cell death is poorly understood but involves the aggregation of alpha-synuclein into Lewy bodies within neurons. Other potential factors involve genetic and environmental influences, medications, lifestyle, and prior health conditions. […] As of 2024, the cause of neurodegeneration in Parkinson’s is unclear, though it is believed to result from the interplay of genetic and environmental factors. The majority of cases are sporadic with no clearly identifiable cause, while approximately 5-10 percent are familial. Around a third of familial cases can be attributed to a single monogenic cause.

• #66 A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson’s disease with insights into screening models | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-023-01047-4

  Microglia and astrocytes can cause neuroinflammation, which can speed the course of pathogenic damage to substantia nigra (SN). The mechanism of Parkinson’s disease (PD) that causes tremors, rigidity, and bradykinesia is a decrease in striatal dopamine. […] The most well-known neurotoxin is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which destroys dopaminergic neurons, resulting in the development of Parkinson’s disease (PD). […] Dopamine auto-oxidation in dopaminergic (DA) neurons is a significant source of reactive oxygen species (ROS) that causes neuronal oxidative stress. […] Most common genes which when affected by mutation lead to development and progression of Parkinson’s disease (PD) are LRRK2, SNCA (alpha-synuclein protein), DJ-1, PRKN (Parkin protein), PINK1, GBA1, and VPS35.

• #67 Parkinson’s disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/parkinsons-disease/

  Parkinson’s disease is a progressive disorder of the nervous system. The disorder affects several regions of the brain, especially an area called the substantia nigra that controls balance and movement. […] Most cases of Parkinson’s disease probably result from a complex interaction of environmental and genetic factors. These cases are classified as sporadic and occur in people with no apparent history of the disorder in their family. The cause of these sporadic cases remains unclear. […] It is not fully understood how genetic changes cause Parkinson’s disease or influence the risk of developing the disorder. Many Parkinson’s disease symptoms occur when nerve cells (neurons) in the substantia nigra die or become impaired. Normally, these cells produce a chemical messenger called dopamine, which transmits signals within the brain to produce smooth physical movements. When these dopamine-producing neurons are damaged or die, communication between the brain and muscles weakens. Eventually, the brain becomes unable to control muscle movement.

• #68 Role of dopamine in the pathophysiology of Parkinson’s disease | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-023-00378-6

  DA impairs the functions of mitochondria, ubiquitinproteasome system (UPS), lysosome and autophagy, resulting in DA neuron vulnerability. […] DA and its derivatives are involved in the toxicity of PD-related neurotoxins, such as rotenone, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and iron species. […] DA is also involved in the PD pathogenesis associated with genetic factors, including SNCA (encoding -synuclein [-syn]), LRRK2 (leucine-rich repeat kinase 2), PINK1 (PTEN-induced kinase 1), Parkin, DJ-1 and GBA1 (glucocerebrosidase-1 [GCase]), contributing to DA neuronal degeneration. […] DA-relevant toxicity in PD pathogenesis has been demonstrated in multiple in vitro and in vivo PD models. […] Direct injection of DA (up to 1 mol) into the rat striatum led to the loss of dopaminergic nerve terminals and the formation of cysteinyl adducts of DA in a DA-dose-dependent manner.

• #69

  https://link.springer.com/article/10.1007/s00018-004-4104-1

  The field of Parkinsons disease pathogenesis is rapidly evolving from the one of a monolithic and obscure entity into the one of a complex scenario with several known molecular players. […] However, most of the progress of the last 5 years has come from the successful mapping and cloning of genes responsible for rare Mendelian variants of Parkinsons disease. […] These discoveries are providing tremendous help in understanding the molecular mechanisms of this devastating disease. […] Moreover, we focus on the mechanisms of disease caused by -synuclein and parkin mutations, and the implications of this growing body of knowledge for understanding the pathogenesis of the common forms of the disease.

• #70 Lipid rafts involvement in the pathogenesis of parkinson’s disease

  https://www.imrpress.com/journal/FBL/20/2/10.2741/4308

  Parkinson’s disease (PD) is one of the most common neurodegenerative diseases affecting an increasing number of people worldwide with the aging society. […] Although the etiology of PD remains largely unknown, it is now clear that genetic factors contribute to the pathogenesis of the disease. […] Recently, several causative genes have been identified in mendelian forms of PD. […] Growing evidence indicates that their gene products play important roles in oxidative stress response, mitochondrial function, and the ubiquitin-proteasome system, which are also implicated in idiopathic PD, suggesting that these gene products share a common pathway to nigral degeneration in both familial and idiopathic PD. […] Interestingly, several lines of evidence show that the gene products associate with lipid rafts which are thought to be involved in important cellular functions such as membrane trafficking, signal transduction, and cytoskeletal organization. […] In this article, we will review studies focusing on PD in association with lipid rafts and discuss implication of lipid rafts in the pathogenesis of PD.

• #71 Lipid rafts involvement in the pathogenesis of parkinson’s disease

  https://www.imrpress.com/journal/FBL/20/2/10.2741/4308

  Parkinson’s disease (PD) is one of the most common neurodegenerative diseases affecting an increasing number of people worldwide with the aging society. […] Although the etiology of PD remains largely unknown, it is now clear that genetic factors contribute to the pathogenesis of the disease. […] Recently, several causative genes have been identified in mendelian forms of PD. […] Growing evidence indicates that their gene products play important roles in oxidative stress response, mitochondrial function, and the ubiquitin-proteasome system, which are also implicated in idiopathic PD, suggesting that these gene products share a common pathway to nigral degeneration in both familial and idiopathic PD. […] Interestingly, several lines of evidence show that the gene products associate with lipid rafts which are thought to be involved in important cellular functions such as membrane trafficking, signal transduction, and cytoskeletal organization. […] In this article, we will review studies focusing on PD in association with lipid rafts and discuss implication of lipid rafts in the pathogenesis of PD.

• #72 Parkinson’s Disease Mechanism Identified | Columbia University Irving Medical Center

  https://www.cuimc.columbia.edu/news/parkinsons-disease-mechanism-identified

  Researchers in the Taub Institute at Columbia University Medical Center (CUMC) have identified a mechanism that appears to underlie the common sporadic (non-familial) form of Parkinsons disease, the progressive movement disorder. […] Studies of rare, familial (heritable) forms of Parkinsons show that a protein called alpha-synuclein plays a role in the development of the disease. […] Using a variety of techniques, including gene-expression analysis and gene-network mapping, the CUMC researchers discovered how common forms of alpha-synuclein contribute to sporadic Parkinsons. […] Some very common genetic variants in the alpha-synuclein gene, present in many people, are known to impact the likelihood that an individual will suffer from sporadic Parkinsons. […] Furthermore, we found that exposure to toxins associated with Parkinson’s can increase the abundance of this longer transcript form of alpha-synuclein.

• #73 Interpreting the dynamic pathogenesis of Parkinson’s disease by longitudinal blood transcriptome analysis | bioRxiv

  https://www.biorxiv.org/content/10.1101/2020.10.26.356204v2

  Achieving an improved understanding of the temporal sequence of factors involved in Parkinson’s disease (PD) pathogenesis may accelerate drug discovery. In this study, we performed a longitudinal transcriptome analysis to identify associated genes underlying the pathogenesis of PD at three temporal phases. We firstly found that multiple initiator genes, which are related to processes of olfactory transduction and stem cell pluripotency, indicate PD risk to those subjects at the prodromal phase. […] And many facilitator genes involved in calcium signaling and stem cell pluripotency contribute to PD onset. […] We next identified 325 aggravator genes whose expression could lead to disease progression through damage to dopaminergic synapses and ferroptosis via an integrative analysis with DNA methylation. […] Last, we made a systematic comparison of gene expression patterns across PD development and accordingly provided candidate drugs at different phases in an attempt to prevent the neurodegeneration process.

• #74 Parkinson’s disease: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/parkinsons-disease/

  Parkinson’s disease is a progressive disorder of the nervous system. The disorder affects several regions of the brain, especially an area called the substantia nigra that controls balance and movement. […] Most cases of Parkinson’s disease probably result from a complex interaction of environmental and genetic factors. These cases are classified as sporadic and occur in people with no apparent history of the disorder in their family. The cause of these sporadic cases remains unclear. […] It is not fully understood how genetic changes cause Parkinson’s disease or influence the risk of developing the disorder. Many Parkinson’s disease symptoms occur when nerve cells (neurons) in the substantia nigra die or become impaired. Normally, these cells produce a chemical messenger called dopamine, which transmits signals within the brain to produce smooth physical movements. When these dopamine-producing neurons are damaged or die, communication between the brain and muscles weakens. Eventually, the brain becomes unable to control muscle movement.

• #75 Environmental and genetic interactions in the pathogenesis of Parkinson’s disease – VJNeurology

  https://www.vjneurology.com/video/t0vr-qhx8i0-environmental-and-genetic-interactions-in-the-pathogenesis-of-parkinsons-disease/

  Caroline Tanner talks on rare high penetrance genes and other more common risk variants that give a genetic predisposition to PD. […] There also may be environmental factors involved in the increased risk of PD, such as exposure to environmental toxicants, specifically chlorinated solvents, and traumatic brain injury. […] Studies have also shown that lifestyle factors such as inactivity may be associated with increased risk of PD. […] Genome-wide studies have suggested that for most people, risk is determined by a complex balance of these factors and their interactions.

• #76 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Parkinsons-Disease-Pathophysiology.aspx

  Certain genes have been found that may be associated with Parkinsons disease. […] Alpha-synculein is the main component of Lewy bodies, which are found in cells of all patients with Parkinson’s disease. In patients with a mutated gene for alpha synculein an altered protein product is formed. This protein accumulates in the cell and attracts other proteins in order to form a deposit which leads to the damage of the neuron. […] These are unstable molecules produced during normal chemical reactions in the body. When they interact with other molecules they have the ability to damage tissues like neurons. […] With age there is a normal decline of the dopamine producing neurons, which leads to the premature loss of dopamine. […] Several toxins like illegal drugs contaminated with a chemical called MPTP may cause severe Parkinson-like symptoms. It was found that once MPTP crossed into the brain it started killing brain cells. […] Other toxins and exposures associated with Parkinsons disease include: manganese dust, carbon disulphide, severe carbon monoxide (CO) poisoning, the insecticides permethrin and beta-hexachlorocyclohexane (beta-HCH), the herbicides paraquat and 2,4-dichlorophenoxyacetic acid and the fungicide maneb.

• #77 ‘Parkinson’s is a man-made disease’: How a chemical Europe can’t quit may be driving the disease – POLITICO

  https://www.politico.eu/article/bas-bloem-parkinsons-pesticides-mptp-glyphosate-paraquat/

  The patients had developed symptoms of late-stage Parkinsons, almost overnight. […] It was like a lightning bolt, Bloem tells me. A single chemical had replicated the entire disease. Parkinsons wasnt just bad luck. It could be caused. […] Parkinsons is a man-made disease, he says. And the tragedy is that were not even trying to prevent it. […] In a 2024 paper co-authored with U.S. neurologist Ray Dorsey, Bloem wrote that Parkinsons is predominantly an environmental disease a condition shaped less by genetics and more by prolonged exposure to toxicants like air pollution, industrial solvents and, above all, pesticides. […] Parkinsons was a very rare disease until the early 20th century, Bloem says. Then with the agricultural revolution, chemical revolution, and the explosion of pesticide use, rates started to climb.

• #78 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Parkinsons-Disease-Pathophysiology.aspx

  Certain genes have been found that may be associated with Parkinsons disease. […] Alpha-synculein is the main component of Lewy bodies, which are found in cells of all patients with Parkinson’s disease. In patients with a mutated gene for alpha synculein an altered protein product is formed. This protein accumulates in the cell and attracts other proteins in order to form a deposit which leads to the damage of the neuron. […] These are unstable molecules produced during normal chemical reactions in the body. When they interact with other molecules they have the ability to damage tissues like neurons. […] With age there is a normal decline of the dopamine producing neurons, which leads to the premature loss of dopamine. […] Several toxins like illegal drugs contaminated with a chemical called MPTP may cause severe Parkinson-like symptoms. It was found that once MPTP crossed into the brain it started killing brain cells. […] Other toxins and exposures associated with Parkinsons disease include: manganese dust, carbon disulphide, severe carbon monoxide (CO) poisoning, the insecticides permethrin and beta-hexachlorocyclohexane (beta-HCH), the herbicides paraquat and 2,4-dichlorophenoxyacetic acid and the fungicide maneb.

• #79 ‘Parkinson’s is a man-made disease’: How a chemical Europe can’t quit may be driving the disease – POLITICO

  https://www.politico.eu/article/bas-bloem-parkinsons-pesticides-mptp-glyphosate-paraquat/

  The patients had developed symptoms of late-stage Parkinsons, almost overnight. […] It was like a lightning bolt, Bloem tells me. A single chemical had replicated the entire disease. Parkinsons wasnt just bad luck. It could be caused. […] Parkinsons is a man-made disease, he says. And the tragedy is that were not even trying to prevent it. […] In a 2024 paper co-authored with U.S. neurologist Ray Dorsey, Bloem wrote that Parkinsons is predominantly an environmental disease a condition shaped less by genetics and more by prolonged exposure to toxicants like air pollution, industrial solvents and, above all, pesticides. […] Parkinsons was a very rare disease until the early 20th century, Bloem says. Then with the agricultural revolution, chemical revolution, and the explosion of pesticide use, rates started to climb.

• #80 ‘Parkinson’s is a man-made disease’: How a chemical Europe can’t quit may be driving the disease – POLITICO

  https://www.politico.eu/article/bas-bloem-parkinsons-pesticides-mptp-glyphosate-paraquat/

  The Netherlands, known for having one of the highest pesticide use rates in Europe, has seen a 30 percent rise in Parkinsons cases over the past decade a slower increase than in some other regions of the world, but still notable, Bloem says. […] To Bloem, reversing the epidemic means shifting the regulatory mindset from reaction to prevention. That means requiring long-term neurotoxicity studies, testing chemical combinations, accounting for real-world exposure, genetic predisposition and the kind of brain damage Parkinsons causes and critically, making manufacturers prove safety, rather than scientists having to prove harm.

• #81 ‘Parkinson’s is a man-made disease’: How a chemical Europe can’t quit may be driving the disease – POLITICO

  https://www.politico.eu/article/bas-bloem-parkinsons-pesticides-mptp-glyphosate-paraquat/

  The Netherlands, known for having one of the highest pesticide use rates in Europe, has seen a 30 percent rise in Parkinsons cases over the past decade a slower increase than in some other regions of the world, but still notable, Bloem says. […] To Bloem, reversing the epidemic means shifting the regulatory mindset from reaction to prevention. That means requiring long-term neurotoxicity studies, testing chemical combinations, accounting for real-world exposure, genetic predisposition and the kind of brain damage Parkinsons causes and critically, making manufacturers prove safety, rather than scientists having to prove harm.

• #82 Ultra-Processed Foods Linked to Accelerated Early Progression of

  https://bioengineer.org/ultra-processed-foods-linked-to-accelerated-early-progression-of-parkinsons-disease/

  MINNEAPOLIS A compelling new study published online in the medical journal Neurology has uncovered a significant association between the consumption of ultra-processed foods and the early indicators of Parkinsons disease. […] The biological underpinnings of how ultra-processed foods might influence neurodegeneration are multifaceted. These foods often contain high levels of refined sugars, trans fats, additives, and preservatives, all of which have been implicated in systemic inflammation, oxidative stress, and metabolic dysregulation. Chronic inflammation and oxidative damage are recognized as contributing factors in the pathogenesis of Parkinsons disease, where dopaminergic neurons in the substantia nigra are particularly vulnerable. […] The findings hint that ultra-processed foods may accelerate neurodegenerative processes with systemic impacts on various neurological pathways before frank motor dysfunction sets in.

• #83 Ultra-Processed Foods Linked to Accelerated Early Progression of

  https://bioengineer.org/ultra-processed-foods-linked-to-accelerated-early-progression-of-parkinsons-disease/

  MINNEAPOLIS A compelling new study published online in the medical journal Neurology has uncovered a significant association between the consumption of ultra-processed foods and the early indicators of Parkinsons disease. […] The biological underpinnings of how ultra-processed foods might influence neurodegeneration are multifaceted. These foods often contain high levels of refined sugars, trans fats, additives, and preservatives, all of which have been implicated in systemic inflammation, oxidative stress, and metabolic dysregulation. Chronic inflammation and oxidative damage are recognized as contributing factors in the pathogenesis of Parkinsons disease, where dopaminergic neurons in the substantia nigra are particularly vulnerable. […] The findings hint that ultra-processed foods may accelerate neurodegenerative processes with systemic impacts on various neurological pathways before frank motor dysfunction sets in.

• #84 Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis – Parkinson’s Disease – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536722/

  Parkinsons disease (PD) is a common neurodegenerative disorder. […] The cause of PD is not known, but a number of genetic risk factors have now been characterized, as well as several genes which cause rare familial forms of PD. […] Several processes have been implicated in PD, including mitochondrial dysfunction, defective protein clearance mechanisms, and neuroinflammation, but the way in which these factors interact remains incompletely understood. […] A number of mechanisms have been implicated in PD pathogenesis, with -synuclein aggregation central to the development of the disease. […] Multiple other processes are thought to be involved, with several studies suggesting that abnormal protein clearance, mitochondrial dysfunction, and neuroinflammation play a role in the onset and progression of PD. […] However, the relationship between these pathways remains unclear.

• #85 Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

  https://www.mdpi.com/1422-0067/23/21/13043

  In the pathogenesis of PD, there are several kinds of disturbances in bioenergetics in the cells of the nigrostriatal system: a decrease in the activity of complex I of the mitochondrial respiratory chain, an increase in the production of ROS by MCh, the ROS-mediated damage to mitochondrial DNA and of other molecules, disturbed mitophagy, followed by various functional disorders of MCh and their host cells. Elevated levels of ROS and energy deficit disrupt the interactions between MCh and ER, reduce the function of lysosomes, and disrupt calcium homeostasis. […] The molecular pathogenesis of sporadic forms includes not only oxidative stress, but also many other pathways and mechanisms: mitochondrial dysfunction, αSyn proteostasis, calcium homeostasis, axonal transport, and neuroinflammation. Mitochondrial dysfunction plays a fundamental and complex role in many neurodegenerative disorders, including PD. PD-associated mitochondrial dysfunction can result from a number of causes, including impairment of mitochondrial biogenesis, increased ROS production, defective mitophagy, compromised trafficking, electron transport chain (ETC) dysfunction, variations to mitochondrial dynamics, calcium imbalance and possibly other indirect influences on mitochondrial function from unrelated pathways.

• #86 Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

  https://www.mdpi.com/1422-0067/23/21/13043

  In the pathogenesis of PD, there are several kinds of disturbances in bioenergetics in the cells of the nigrostriatal system: a decrease in the activity of complex I of the mitochondrial respiratory chain, an increase in the production of ROS by MCh, the ROS-mediated damage to mitochondrial DNA and of other molecules, disturbed mitophagy, followed by various functional disorders of MCh and their host cells. Elevated levels of ROS and energy deficit disrupt the interactions between MCh and ER, reduce the function of lysosomes, and disrupt calcium homeostasis. […] The molecular pathogenesis of sporadic forms includes not only oxidative stress, but also many other pathways and mechanisms: mitochondrial dysfunction, αSyn proteostasis, calcium homeostasis, axonal transport, and neuroinflammation. Mitochondrial dysfunction plays a fundamental and complex role in many neurodegenerative disorders, including PD. PD-associated mitochondrial dysfunction can result from a number of causes, including impairment of mitochondrial biogenesis, increased ROS production, defective mitophagy, compromised trafficking, electron transport chain (ETC) dysfunction, variations to mitochondrial dynamics, calcium imbalance and possibly other indirect influences on mitochondrial function from unrelated pathways.

• #87 Role of dopamine in the pathophysiology of Parkinson’s disease | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-023-00378-6

  The enhanced mitochondrial oxidative stress leads to DA oxidation with generation of DAQs, conjugation of DAQs with GBA1, inhibition of GBA1 enzymatic activity, lysosomal dysfunction, and accumulation of deleterious -syn protein. […] DOPAL is also reactive and can be an endogenous neurotoxin due to the presence of its both aldehyde and catechol moieties. […] The neurotoxicity of DOPAL has been reported in various studies both in vitro and in vivo. […] DOPAL can conjugate through its aldehyde moiety with lysine residues of proteins via the SB reaction. […] The conjugation of DOPAL to lysine residues interferes with many cellular events and down-regulates cell viability, as evidenced by ubiquitin oligomerization, accumulation of ubiquitinated proteins and impairment of UPS functions upon DOPAL challenges.

• #88 Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

  https://www.mdpi.com/1422-0067/23/21/13043

  In the pathogenesis of PD, there are several kinds of disturbances in bioenergetics in the cells of the nigrostriatal system: a decrease in the activity of complex I of the mitochondrial respiratory chain, an increase in the production of ROS by MCh, the ROS-mediated damage to mitochondrial DNA and of other molecules, disturbed mitophagy, followed by various functional disorders of MCh and their host cells. Elevated levels of ROS and energy deficit disrupt the interactions between MCh and ER, reduce the function of lysosomes, and disrupt calcium homeostasis. […] The molecular pathogenesis of sporadic forms includes not only oxidative stress, but also many other pathways and mechanisms: mitochondrial dysfunction, αSyn proteostasis, calcium homeostasis, axonal transport, and neuroinflammation. Mitochondrial dysfunction plays a fundamental and complex role in many neurodegenerative disorders, including PD. PD-associated mitochondrial dysfunction can result from a number of causes, including impairment of mitochondrial biogenesis, increased ROS production, defective mitophagy, compromised trafficking, electron transport chain (ETC) dysfunction, variations to mitochondrial dynamics, calcium imbalance and possibly other indirect influences on mitochondrial function from unrelated pathways.

• #89 Current understanding of the molecular mechanisms in Parkinson’s disease: Targets for potential treatments | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-017-0099-z

  PD is a multifactorial disease, where both genetic and non-genetic, such as environmental factors, are involved. The most salient mechanisms involved in the development of PD include the accumulation of misfolded proteins aggregates, failure of protein clearance pathways, mitochondrial damage, oxidative stress, excitotoxicity, neuroinflammation, and genetic mutations. […] One of the hallmark pathologies of PD is the intracellular accumulation of LB in DA neurons of the SNpc, which contain misfolded aggregates of SNCA and other associated proteins. […] The oligomers, proto-fibrils, and fibrils of SNCA or other misfolded amyloid proteins can make a pore in the membrane, causing neuronal death via oxidative stress, energy failure, excitotoxicity, and neuroinflammation. […] The p-tau can also be co-localized with LB, which is often associated with the development of sporadic PD. […] Although NFTs are associated most closely with AD, they can co-localize with SNCA in LB and play an important role in destabilization of DA-neuronal architecture, which ultimately leads to rapid degeneration and death of DA neurons.

• #90 Pathogenesis and current therapeutic approaches for Parkinson’s disease

  https://accscience.com/journal/GTM/3/4/10.36922/gtm.5082

  Parkinsons disease (PD) is a common neurodegenerative disorder among the elderly, characterized by a spectrum of motor and non-motor symptoms. […] Recent advancements in understanding the pathogenesis of PD have catalyzed the development of innovative treatment strategies. […] Emerging therapies, including gene therapy and stem cell therapy, offer transformative potential by addressing the underlying disease mechanisms. […] This review summarizes the latest research progress in the understanding of PD pathogenesis and treatment, aiming to provide guidance for the clinical management of PD.

• #91 2. Pathophysiology of Parkinson’s Disease | ATrain Education

  https://www.atrainceu.com/content/2-pathophysiology-parkinson%E2%80%99s-disease

  Although we are learning more each day about the pathophysiology of Parkinsons disease, it is still considered largely idiopathic (of unknown cause). It likely involves the interaction of host susceptibility and environmental factors. A small percentage of cases are genetically linked and genetic factors are being intensely studied. […] Parkinsons is increasingly seen as a complex neurodegenerative disease with a sequence of progression. There is strong evidence that it first affects the dorsal motor nucleus of the vagus nerve and the olfactory bulbs and nucleus, then the locus coeruleus, and eventually the substantia nigra. […] Damage to these various neuronal systems account for the multi-faceted pathophysiologic changes that cause impairments not just to the motor system but also to the cognitive and neuropsychological systems (Kwan Whitehill, 2011).

• #92 2. Pathophysiology of Parkinson’s Disease | ATrain Education

  https://www.atrainceu.com/content/2-pathophysiology-parkinson%E2%80%99s-disease

  Although we are learning more each day about the pathophysiology of Parkinsons disease, it is still considered largely idiopathic (of unknown cause). It likely involves the interaction of host susceptibility and environmental factors. A small percentage of cases are genetically linked and genetic factors are being intensely studied. […] Parkinsons is increasingly seen as a complex neurodegenerative disease with a sequence of progression. There is strong evidence that it first affects the dorsal motor nucleus of the vagus nerve and the olfactory bulbs and nucleus, then the locus coeruleus, and eventually the substantia nigra. […] Damage to these various neuronal systems account for the multi-faceted pathophysiologic changes that cause impairments not just to the motor system but also to the cognitive and neuropsychological systems (Kwan Whitehill, 2011).

• #93 Pathophysiology of non-motor signs in Parkinsons disease: some recent updating with brief presentation

  https://www.explorationpub.com/Journals/ent/Article/100436

  In summary, olfactory deficits are among the earliest non-motor signs of PD. They seem to be due to the deposition of -syn in the OB and anterior olfactory nucleus. From there, -syn spreads by a prion-like mechanism to other brain regions including SN. […] The underlying mechanisms of PD psychosis remain poorly understood and it may result from the interplay of neuronal degeneration, and abnormalities in neurochemical transmitters and neural structures. […] However, PD has been recognized as a motor disease since its discovery, it is now recognized as a multisystem disorder combining both motor and non-motor signs. Non-motor signs are usually attributed to neurobiological, medical and psychological factors. Their impact is greater than motor signs particularly in the late stage of the disease. Research on how to diagnose and control non-motor signs is of great importance to improve patients quality of life.

• #94 2. Pathophysiology of Parkinson’s Disease | ATrain Education

  https://www.atrainceu.com/content/2-pathophysiology-parkinson%E2%80%99s-disease

  Although we are learning more each day about the pathophysiology of Parkinsons disease, it is still considered largely idiopathic (of unknown cause). It likely involves the interaction of host susceptibility and environmental factors. A small percentage of cases are genetically linked and genetic factors are being intensely studied. […] Parkinsons is increasingly seen as a complex neurodegenerative disease with a sequence of progression. There is strong evidence that it first affects the dorsal motor nucleus of the vagus nerve and the olfactory bulbs and nucleus, then the locus coeruleus, and eventually the substantia nigra. […] Damage to these various neuronal systems account for the multi-faceted pathophysiologic changes that cause impairments not just to the motor system but also to the cognitive and neuropsychological systems (Kwan Whitehill, 2011).

• #95 Pathophysiology of non-motor signs in Parkinsons disease: some recent updating with brief presentation

  https://www.explorationpub.com/Journals/ent/Article/100436

  Parkinsons disease (PD) is a progressive neurodegenerative disorder affecting 1% of the population above sixty years. It is caused by an interaction between genetic and environmental risk factors. Loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) is pathologically characterizing the disease and responsible for the cardinal motor symptoms, most notably, bradykinesia, rest tremors, rigidity, and loss of postural reflexes. […] The present general review aimed to briefly update non-motor signs and their underlying pathophysiology in PD. […] The pathological hallmarks of the disease include the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of eosinophilic protein deposits, Lewy bodies (LBs), in the nigrostriatal region, other aminergic nuclei, and cortical and limbic structures. […] The response of motor signs to L-dopa makes non-motor signs the main contributors to patients disability in PD. Non-motor signs occur earlier than motor symptoms and their targeted detection can play an important role in the identification of PD patients and in developing novel neuroprotective therapies.

• #96 Study Uncovers Biological Mechanism Behind Loss of Smell in Parkinson’s Patients < Yale School of Medicine

  https://medicine.yale.edu/news-article/new-study-uncovers-biological-mechanism-behind-loss-of-smell-in-parkinsons-patients/

  Parkinsons disease is an illness well known for its motor symptomstremor, stiffness, and slowness of movement. […] About 75-90 percent of Parkinsons patients report diminishing sense of smell, even prior to the onset of motor symptoms, and is now recognized a non-motor symptom of Parkinsons disease. […] Researchers at the Greer Lab and Chandra Lab at Yale School of Medicine determined the biological mechanisms behind this olfactory impairment by using an alpha-synuclein A30P mouse model used to mimic symptoms of Parkinsons in mice. […] They found that those mice with olfactory deficits exhibited severe pathology in projection neurons of the olfactory pathway. […] They also found these mice showed reduced neurogenesis in the olfactory bulb. […] However, since the motor symptoms of the disease were more debilitating, very little research had been done to understand the underlying biological mechanism of the olfactory dimension. […] We are excited to begin to understand the basis of anosmia in Parkinsons disease patients, says Sreeganga Chandra, PhD, associate professor of neurology and neuroscience. […] People that are diagnosed with Parkinsons disease would report loss of smell up to 10 years before their diagnosis.

• #97 Study Uncovers Biological Mechanism Behind Loss of Smell in Parkinson’s Patients < Yale School of Medicine

  https://medicine.yale.edu/news-article/new-study-uncovers-biological-mechanism-behind-loss-of-smell-in-parkinsons-patients/

  Parkinsons disease is an illness well known for its motor symptomstremor, stiffness, and slowness of movement. […] About 75-90 percent of Parkinsons patients report diminishing sense of smell, even prior to the onset of motor symptoms, and is now recognized a non-motor symptom of Parkinsons disease. […] Researchers at the Greer Lab and Chandra Lab at Yale School of Medicine determined the biological mechanisms behind this olfactory impairment by using an alpha-synuclein A30P mouse model used to mimic symptoms of Parkinsons in mice. […] They found that those mice with olfactory deficits exhibited severe pathology in projection neurons of the olfactory pathway. […] They also found these mice showed reduced neurogenesis in the olfactory bulb. […] However, since the motor symptoms of the disease were more debilitating, very little research had been done to understand the underlying biological mechanism of the olfactory dimension. […] We are excited to begin to understand the basis of anosmia in Parkinsons disease patients, says Sreeganga Chandra, PhD, associate professor of neurology and neuroscience. […] People that are diagnosed with Parkinsons disease would report loss of smell up to 10 years before their diagnosis.

• #98 Interpreting the dynamic pathogenesis of Parkinson’s disease by longitudinal blood transcriptome analysis | bioRxiv

  https://www.biorxiv.org/content/10.1101/2020.10.26.356204v2

  Achieving an improved understanding of the temporal sequence of factors involved in Parkinson’s disease (PD) pathogenesis may accelerate drug discovery. In this study, we performed a longitudinal transcriptome analysis to identify associated genes underlying the pathogenesis of PD at three temporal phases. We firstly found that multiple initiator genes, which are related to processes of olfactory transduction and stem cell pluripotency, indicate PD risk to those subjects at the prodromal phase. […] And many facilitator genes involved in calcium signaling and stem cell pluripotency contribute to PD onset. […] We next identified 325 aggravator genes whose expression could lead to disease progression through damage to dopaminergic synapses and ferroptosis via an integrative analysis with DNA methylation. […] Last, we made a systematic comparison of gene expression patterns across PD development and accordingly provided candidate drugs at different phases in an attempt to prevent the neurodegeneration process.

• #99 Interpreting the dynamic pathogenesis of Parkinson’s disease by longitudinal blood transcriptome analysis | bioRxiv

  https://www.biorxiv.org/content/10.1101/2020.10.26.356204v2

  Achieving an improved understanding of the temporal sequence of factors involved in Parkinson’s disease (PD) pathogenesis may accelerate drug discovery. In this study, we performed a longitudinal transcriptome analysis to identify associated genes underlying the pathogenesis of PD at three temporal phases. We firstly found that multiple initiator genes, which are related to processes of olfactory transduction and stem cell pluripotency, indicate PD risk to those subjects at the prodromal phase. […] And many facilitator genes involved in calcium signaling and stem cell pluripotency contribute to PD onset. […] We next identified 325 aggravator genes whose expression could lead to disease progression through damage to dopaminergic synapses and ferroptosis via an integrative analysis with DNA methylation. […] Last, we made a systematic comparison of gene expression patterns across PD development and accordingly provided candidate drugs at different phases in an attempt to prevent the neurodegeneration process.

• #100 Parkinson’s Disease: A Review about Pathogenesis, Treatment and Experimental Models

  https://aprh.journals.ekb.eg/article_8013.html

  Parkinson disease (PD) is the second most common age-related neurodegenerative disease after Alzheimer disease, characterized by loss of dopaminergic neurons in substantia nigra pars compacta, accompanied by motor and non-motor symptoms. […] However, the etiology of the disease is still undefined; several studies assume that oxidative stress, mitochondrial defects, neuroinflammation, apoptosis and excitotoxicity play vital roles in the pathogenesis and progress of the disease. […] The presence of intraneuronal proteinaceous cytoplasmic inclusions Lewy Bodies and the loss of the nigrostriatal dopaminergic neurons are the main neuropathological hallmarks of PD. […] Experimental models of PD can be induced by several neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 6-hydroxydopamine, rotenone and paraquat which produce neuropathological and neurochemical changes that are identical to those seen in PD.

• #101 A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson’s disease with insights into screening models | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-023-01047-4

  The commonly used neurotoxin models for inducing Parkinson’s disease are 6-hydroxydopamine (6-OHDA), rotenone, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and genetic models. […] The degradation of neurons is triggered by gene mutations that encode for central nervous system (CNS) proteins. In particular, SNCA (alpha-synuclein protein) turns self-aggregates and abnormal. […] PD can result from a variety of dysfunctional processes, such as mitochondrial disease or unique oxidative stress caused by reactive oxygen species (ROS), which results in neuronal degeneration. […] A dopaminergic imbalance causes the novel neurodegenerative disease PD to cause mobility deficits (inhibitory D2 and excitatory D1 receptors). […] The neurochemical basis of PD is the ensuing reduction in striatal dopamine.

• #102 A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson’s disease with insights into screening models | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-023-01047-4

  The induction of the disease by various models has been successfully studied for understanding the genesis, propagation and treatment. […] Hence, substances like 6-hydroxydopamine, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone, and methamphetamine are successfully used for inducing neurotoxicity to develop signs and symptoms like Parkinson’s disease as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine targets mitochondrial cells and serves as an excellent model for how aberrant mitochondrial function can result in symptoms like those of Parkinson’s disease. […] According to our opinion, the purpose of clinical studies should be to postpone motor difficulties before they manifest ever lasting effects. Finding new multitarget medications or therapies without side effects is becoming more difficult, whereas the rate of Parkinson’s disease occurrence globally is rising quickly. Future investigations of these molecular pathways will be essential for designing disease-specific therapeutics.

• #103 A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson’s disease with insights into screening models | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-023-01047-4

  The commonly used neurotoxin models for inducing Parkinson’s disease are 6-hydroxydopamine (6-OHDA), rotenone, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and genetic models. […] The degradation of neurons is triggered by gene mutations that encode for central nervous system (CNS) proteins. In particular, SNCA (alpha-synuclein protein) turns self-aggregates and abnormal. […] PD can result from a variety of dysfunctional processes, such as mitochondrial disease or unique oxidative stress caused by reactive oxygen species (ROS), which results in neuronal degeneration. […] A dopaminergic imbalance causes the novel neurodegenerative disease PD to cause mobility deficits (inhibitory D2 and excitatory D1 receptors). […] The neurochemical basis of PD is the ensuing reduction in striatal dopamine.

• #104 Investigating the Mechanism of Pathology in Parkinson’s Disease – Azure Biosystems

  https://azurebiosystems.com/blog/investigating-the-mechanism-of-pathology-in-parkinsons-disease/

  Parkinson’s disease (PD) is an age-related neurodegenerative disorder that affects almost 1 million people in the United States. PD is associated with motor symptoms including tremors and stiffness that affect balance and coordination. Symptoms appear as dopaminergic neurons are lost from the midbrain. Neuronal death appears to be due to the accumulation of toxic aggregates, called Lewy bodies, of the protein alpha-synuclein in neurons. […] In recent work, Anandhan et al investigated the role of a transcription factor, NRF2, in alpha-synuclein driven pathology. NRF2 is known to regulate the cellular stress response and lack of NRF2 has been shown to exacerbate PD pathology, but the precise roll of NRF2 in alpha-synuclein driven pathology is unknown. The authors created mice that overexpress human alpha-synuclein as a model of PD. They then knocked out the gene coding for NRF2 so study the effect of the loss of NRF2 on behavioral tests, neuron loss in several brain regions, and phosphorylation and oligomerization of alpha-synuclein.

• #105 A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson’s disease with insights into screening models | Bulletin of the National Research Centre | Full Text

  https://bnrc.springeropen.com/articles/10.1186/s42269-023-01047-4

  The induction of the disease by various models has been successfully studied for understanding the genesis, propagation and treatment. […] Hence, substances like 6-hydroxydopamine, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone, and methamphetamine are successfully used for inducing neurotoxicity to develop signs and symptoms like Parkinson’s disease as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine targets mitochondrial cells and serves as an excellent model for how aberrant mitochondrial function can result in symptoms like those of Parkinson’s disease. […] According to our opinion, the purpose of clinical studies should be to postpone motor difficulties before they manifest ever lasting effects. Finding new multitarget medications or therapies without side effects is becoming more difficult, whereas the rate of Parkinson’s disease occurrence globally is rising quickly. Future investigations of these molecular pathways will be essential for designing disease-specific therapeutics.

• #106 Investigating the Mechanism of Pathology in Parkinson’s Disease – Azure Biosystems

  https://azurebiosystems.com/blog/investigating-the-mechanism-of-pathology-in-parkinsons-disease/

  Parkinson’s disease (PD) is an age-related neurodegenerative disorder that affects almost 1 million people in the United States. PD is associated with motor symptoms including tremors and stiffness that affect balance and coordination. Symptoms appear as dopaminergic neurons are lost from the midbrain. Neuronal death appears to be due to the accumulation of toxic aggregates, called Lewy bodies, of the protein alpha-synuclein in neurons. […] In recent work, Anandhan et al investigated the role of a transcription factor, NRF2, in alpha-synuclein driven pathology. NRF2 is known to regulate the cellular stress response and lack of NRF2 has been shown to exacerbate PD pathology, but the precise roll of NRF2 in alpha-synuclein driven pathology is unknown. The authors created mice that overexpress human alpha-synuclein as a model of PD. They then knocked out the gene coding for NRF2 so study the effect of the loss of NRF2 on behavioral tests, neuron loss in several brain regions, and phosphorylation and oligomerization of alpha-synuclein.

• #107 Common molecular mechanism of Parkinson’s pathology discovered in study | News Center

  https://med.stanford.edu/news/all-news/2016/09/common-molecular-mechanism-of-parkinsons-pathology-discovered.html

  Malfunctioning mitochondria are like old jalopies: Their fuel efficiency is rotten, and they spew out tons of toxic exhaust in the form of corrosive chemicals called free radicals. […] The researchers discovered that Miro’s removal can occur only after LRRK2 forms a complex with Miro. […] Defective LRRK2 is impaired in forming this complex, resulting in significant delays in Miro’s removal. […] But in the dopaminergic nerve cells derived from the cells of patients with LRRK2G2019S-mutant Parkinson’s, this process and the key steps leading up to it were substantially delayed. […] When the researchers biochemically induced excessive free-radical production in the nerve cells, those from every Parkinson’s patient sampled – familial and sporadic alike – died in much greater numbers than equivalent cells derived from healthy patients.

• #108 Parkinson’s Disease Mechanism Discovered | HHMI

  https://www.hhmi.org/news/parkinsons-disease-mechanism-discovered

  Lindquist and her colleagues believe their findings will guide the search for new drugs that suppress alpha-synuclein toxicity by enhancing the machinery of ER-to-Golgi transport. […] Current treatments for Parkinsons disease do not aim at protecting the dopamine-producing neurons themselves. […] However, given the fact that weve found the same results in yeast, flies, worms and rat neurons, I would be very surprised if we didnt find that they were relevant in humans, she said. […] These results highlight the value and importance of very simple model organisms in studying these disorders, she said.

• #109 Parkinson’s Disease Mechanism Discovered | HHMI

  https://www.hhmi.org/news/parkinsons-disease-mechanism-discovered

  Defects in a critical cellular pathway can lead to symptoms of Parkinsons disease. […] Howard Hughes Medical Institute researchers have pinpointed defects in a critical cellular pathway that can lead to the death of dopamine-producing nerve cells and ultimately symptoms of Parkinsons disease. […] According to the researchers, the findings offer a promising opportunity for developing new drugs to treat the underlying causes of Parkinsons disease and related neurodegenerative disorders. […] The researchers’ began their experiments seeking to clarify the role of the protein alpha-synuclein in Parkinsons disease. […] Researchers also knew that accumulation of alpha-synuclein caused neurodegeneration in animal models of Parkinsons disease, but little was known about alpha-synucleins normal cellular function or how it contributed to disease.

• #110 Pathogenesis and current therapeutic approaches for Parkinson’s disease

  https://accscience.com/journal/GTM/3/4/10.36922/gtm.5082

  Parkinsons disease (PD) is a common neurodegenerative disorder among the elderly, characterized by a spectrum of motor and non-motor symptoms. […] Recent advancements in understanding the pathogenesis of PD have catalyzed the development of innovative treatment strategies. […] Emerging therapies, including gene therapy and stem cell therapy, offer transformative potential by addressing the underlying disease mechanisms. […] This review summarizes the latest research progress in the understanding of PD pathogenesis and treatment, aiming to provide guidance for the clinical management of PD.

• #111 Researcher Identifies Key Mechanism in Parkinson’s Disease Research – UConn Today

  https://today.uconn.edu/2023/08/researcher-identifies-key-mechanism-in-parkinsons-disease-research/

  Yulan Xiong and her team have made a novel discovery about how a gene responsible for Parkinson’s Disease in many cases can be regulated. […] Yulan Xiong discovered that a critical mechanism for regulating a gene associated with Parkinson’s Disease occurs at the mRNA level when DNA transcripts itself. […] Scientists have known that, in most familial cases, Parkinsons Disease is caused by a genetic mutation in a gene called LRRK2. […] With Parkinsons disease, mutation to LRRK2 does not cause the protein it codes for, daradarin, to become deformed. Instead, the body begins producing too much of the protein. […] Until now, scientists did not know how to control this protein expression because they didnt understand the mechanisms underlying it. […] The Xiong lab has solved this mystery with their novel study identifying an LRRK2 regulator, an enzyme called ATIC, and a potential pharmaceutical treatment.

• #112 Promising Parkinson’s drug decoded

  https://medicalxpress.com/news/2025-05-parkinson-drug-decoded.html

  Inhibition of the deubiquitinase USP30 promotes mitophagy and thus mitochondrial renewal in dopaminergic nerve cells and could therefore form the basis for an innovative therapy for Parkinson’s disease. […] Impaired quality control of mitochondria plays a central role in Parkinson’s disease. […] The exact cause of nerve cell death remains unclear. However, there are indications that defects in their mitochondria could be responsible. Nerve cells in particular are highly dependent on these organelles, as they require high amounts of energy. […] An important enzyme in mitophagy is the deubiquitinase (DUB) USP30. It removes ubiquitin marks from defective mitochondria that are destined for degradation. […] An inhibitor of this enzyme, which could promote mitophagy and thus improve nerve function, is currently being investigated in clinical trials: It is considered a promising candidate drug for the treatment of Parkinson’s disease and chronic kidney disease.

• #113 Pathogenesis and current therapeutic approaches for Parkinson’s disease

  https://accscience.com/journal/GTM/3/4/10.36922/gtm.5082

  Parkinsons disease (PD) is a common neurodegenerative disorder among the elderly, characterized by a spectrum of motor and non-motor symptoms. […] Recent advancements in understanding the pathogenesis of PD have catalyzed the development of innovative treatment strategies. […] Emerging therapies, including gene therapy and stem cell therapy, offer transformative potential by addressing the underlying disease mechanisms. […] This review summarizes the latest research progress in the understanding of PD pathogenesis and treatment, aiming to provide guidance for the clinical management of PD.

• #114 Poly (ADP-ribose) in the pathogenesis of Parkinson’s disease

  https://www.bmbreports.org/journal/view.html?spage=424&volume=47&number=8

  The defining feature of Parkinson’s disease is a progressive and selective demise of dopaminergic neurons. A recent report on Parkinson’s disease animal model demonstrates that poly (ADP-ribose) (PAR) dependent cell death, also named parthanatos, is accountable for selective dopaminergic neuronal loss. Parthanatos is a programmed necrotic cell death, characterized by PARP1 activation, apoptosis inducing factor (AIF) nuclear translocation, and large scale DNA fragmentation. […] In this review, we will discuss the roles of PARP1 activation and PAR molecules in the pathological processes of Parkinson’s disease. Potential interaction between PAR molecule and Parkinson’s disease protein interactome are briefly introduced. Finally, we suggest promising points of therapeutic intervention in the pathological PAR signaling cascade to halt progression in Parkinson’s disease.

• #115 New Mechanism Behind Parkinson’s Disease Revealed | Okinawa Institute of Science and Technology OIST

  https://www.oist.jp/news-center/press-releases/new-mechanism-behind-parkinson%E2%80%99s-disease-revealed

  Researchers have identified the toxic mechanism at work during an overabundance of alpha-synuclein, a protein linked to Parkinsons disease, in neurons. […] Researchers at the Okinawa Institute of Science and Technology Graduate University (OIST) have found that the protein hinders a key step involved in the transmission of neuronal signals, which is essential for higher-brain functioning: vesicle endocytosis at the nerve terminal. […] The retrieval of an emptied vesicle membrane is called endocytosis, and it is this process that an overabundance of alpha-synuclein disrupts. Endocytosis is critical for proper neurotransmissionwhen it is inhibited, the rest of the steps involved in transmission are affected as well. […] A deeper look into the mechanism by which alpha-synuclein inhibits endocytosis revealed toxic effects of the over-assembly of microtubules. […] Researchers believe that this inhibitory process caused by an overabundance of alpha-synuclein is what occurs in the early stages of Parkinsons disease, before morphological changes such as the loss of function and death of neurons begins.

• #116 Common molecular mechanism of Parkinson’s pathology discovered in study | News Center

  https://med.stanford.edu/news/all-news/2016/09/common-molecular-mechanism-of-parkinsons-pathology-discovered.html

  Remarkably, the scientists discovered they could prevent the delay in Parkinson’s-derived nerve cells’ dismantling of faulty mitochondria, as well as forestall those cells’ untimely death in the face of free-radical onslaught. […] Medicines that lower Miro levels could prove beneficial in treating the disease. […] Wang’s team also proved that LRRK2 is recruited to sites of mitochondrial stress. […] They believe many different intracellular difficulties can contribute to the failure of even a perfectly normal LRRK2 complex with Miro, and that Miro’s resultant failure to release its grip may be a reliable early biomarker – and possibly the crucial causal event – of Parkinson’s disease. […] Measuring Miro levels in skin fibroblasts from people at risk of Parkinson’s might someday prove beneficial in getting an accurate, early diagnosis.

• #117 Parkinson’s disease – Diagnosis and treatment – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/parkinsons-disease/diagnosis-treatment/drc-20376062

  Alpha-synuclein is found in Lewy bodies. It forms clumps that the body can’t break down. The clumps spread and damage brain cells. […] In a 2023 study, researchers tested the spinal fluid of more than 1,000 people to look for clumps of the protein alpha-synuclein. The test accurately identified people with Parkinson’s disease 87.7% of the time. The test also was highly sensitive for detecting people at risk of Parkinson’s disease. […] This study of the alpha-synuclein seed amplification assay was the largest so far. Some researchers say the study may be a breakthrough for Parkinson’s disease diagnosis, research and treatment trials. But larger studies are needed. […] There’s hope among researchers that in the future, the test could be done using blood samples rather than spinal fluid.

• #118 Researcher Identifies Key Mechanism in Parkinson’s Disease Research – UConn Today

  https://today.uconn.edu/2023/08/researcher-identifies-key-mechanism-in-parkinsons-disease-research/

  The ATIC enzyme was regulating LRRK2 at the mRNA level, not at the protein level. […] ATIC substrate brings in a binding protein called AUF-1 to specific regions of LRRK2 mRNA. AUF-1 then recruits another DCP1/2 enzyme complex. Together they are able to reduce LRRK2 levels. […] Xiong and her lab discovered that AICAr, the precursor of ATIC substrate, a drug that mimics ATIC activity, can significantly repress LRRK2 levels. […] Our study is the first to find out the mechanism, Xiong says. Its also important that we identified the compound, that can directly decrease LRRK2 levels which means that we can use this compound to treat Parkinsons patients. […] AICAr has shown promise in preclinical trials as a treatment for metabolic disorders, cardiovascular diseases, and other conditions. But AICAr could not pass through the blood-brain barrier, a major limitation for its use treating Parkinsons Disease. […] Xiong and her collaborators are currently working on modifying AICAr to overcome this challenge.

• #119 Researcher Identifies Key Mechanism in Parkinson’s Disease Research – UConn Today

  https://today.uconn.edu/2023/08/researcher-identifies-key-mechanism-in-parkinsons-disease-research/

  The ATIC enzyme was regulating LRRK2 at the mRNA level, not at the protein level. […] ATIC substrate brings in a binding protein called AUF-1 to specific regions of LRRK2 mRNA. AUF-1 then recruits another DCP1/2 enzyme complex. Together they are able to reduce LRRK2 levels. […] Xiong and her lab discovered that AICAr, the precursor of ATIC substrate, a drug that mimics ATIC activity, can significantly repress LRRK2 levels. […] Our study is the first to find out the mechanism, Xiong says. Its also important that we identified the compound, that can directly decrease LRRK2 levels which means that we can use this compound to treat Parkinsons patients. […] AICAr has shown promise in preclinical trials as a treatment for metabolic disorders, cardiovascular diseases, and other conditions. But AICAr could not pass through the blood-brain barrier, a major limitation for its use treating Parkinsons Disease. […] Xiong and her collaborators are currently working on modifying AICAr to overcome this challenge.

• #120 Parkinson’s Disease: Etiology, Neuropathology, and Pathogenesis – Parkinson’s Disease – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK536722/

  Parkinsons disease (PD) is a common neurodegenerative disorder. […] The cause of PD is not known, but a number of genetic risk factors have now been characterized, as well as several genes which cause rare familial forms of PD. […] Several processes have been implicated in PD, including mitochondrial dysfunction, defective protein clearance mechanisms, and neuroinflammation, but the way in which these factors interact remains incompletely understood. […] A number of mechanisms have been implicated in PD pathogenesis, with -synuclein aggregation central to the development of the disease. […] Multiple other processes are thought to be involved, with several studies suggesting that abnormal protein clearance, mitochondrial dysfunction, and neuroinflammation play a role in the onset and progression of PD. […] However, the relationship between these pathways remains unclear.

• #121 BIOCELL | The pathogenesis of Parkinson’s disease and crosstalk with other diseases

  https://www.techscience.com/biocell/v48n8/57515

  In China, Parkinsons disease (PD) is the second most prevalent central nervous system (CNS) degenerative illness affecting middle-aged and older persons. […] The environment, genetics, mitochondrial dysfunction, oxidative stress, inflammation, protein aggregation and misfolding, loss of trophic factors, cell death, and gut microbiota may all have a role in the etiology of PD. […] This article reviews the pathogenesis of PD, its correlations with other non-genetic diseases, and the research progress of drugs and technologies for alleviating PD.

• #122 The pathogenesis of Parkinson’s disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/38245249/

  Parkinson’s disease is a progressive neurodegenerative condition associated with the deposition of aggregated -synuclein. Insights into the pathogenesis of Parkinson’s disease have been derived from genetics and molecular pathology. […] Biochemical studies, investigation of transplanted neurons in patients with Parkinson’s disease, and cell and animal model studies suggest that abnormal aggregation of -synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson’s disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson’s disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson’s disease. Although there are currently no disease-modifying treatments for Parkinson’s disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.

• #123 Signaling pathways in Parkinson’s disease: molecular mechanisms and therapeutic interventions | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-023-01353-3

  The primary pathogenic characteristics of PD include the steady degradation of just a subset of neurons within particular brain areas, such as the SN, as the illness progresses. Dopaminergic neurons are lost exclusively in the ventrolateral SN in the early stages; however, this damage spreads in the late stages. […] Abnormal -synuclein aggregation is one of the most important hypotheses explaining the death of nigrostriatal neurons in PD. […] Oxidative stress (OS) is a major process in aging that directly harms the CNS. […] Mitochondrial dysfunction is increasingly understood to be important in PD pathogenesis. […] Neuroinflammation-related damage in patients with PD. […] The role of gut microbiota in neurological diseases has attracted considerable interest. […] The mechanisms involved in PD are very complex, such as the aggregation of -synuclein, OS, neuroinflammation, ferroptosis, mitochondrial dysfunction, gut dysbiosis, etc.

• #124 Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

  https://www.mdpi.com/1422-0067/23/21/13043

  In the pathogenesis of PD, there are several kinds of disturbances in bioenergetics in the cells of the nigrostriatal system: a decrease in the activity of complex I of the mitochondrial respiratory chain, an increase in the production of ROS by MCh, the ROS-mediated damage to mitochondrial DNA and of other molecules, disturbed mitophagy, followed by various functional disorders of MCh and their host cells. Elevated levels of ROS and energy deficit disrupt the interactions between MCh and ER, reduce the function of lysosomes, and disrupt calcium homeostasis. […] The molecular pathogenesis of sporadic forms includes not only oxidative stress, but also many other pathways and mechanisms: mitochondrial dysfunction, αSyn proteostasis, calcium homeostasis, axonal transport, and neuroinflammation. Mitochondrial dysfunction plays a fundamental and complex role in many neurodegenerative disorders, including PD. PD-associated mitochondrial dysfunction can result from a number of causes, including impairment of mitochondrial biogenesis, increased ROS production, defective mitophagy, compromised trafficking, electron transport chain (ETC) dysfunction, variations to mitochondrial dynamics, calcium imbalance and possibly other indirect influences on mitochondrial function from unrelated pathways.

• #125 Parkinson’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Parkinson%27s_disease

  Molecularly, abnormal aggregation of alpha-synuclein is considered a key contributor to PD pathogenesis, although the trigger for this aggregation is debated. Proteostasis disruption and the dysfunction of cell organelles, including endosomes, lysosomes, and mitochondria, are implicated in pathogenesis. Additionally, maladaptive immune and inflammatory responses are potential contributors. The substantial heterogeneity in PD presentation and progression suggests the involvement of multiple interacting triggers and pathogenic pathways. […] Parkinson’s disease has two hallmark pathophysiological processes: the abnormal aggregation of alpha-synuclein that leads to Lewy pathology, and the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The death of these neurons reduces available dopamine in the striatum, which in turn affects circuits controlling movement in the basal ganglia. By the time motor symptoms appear, 50-80 percent of all dopaminergic neurons in the substantia nigra have degenerated.

• #126 Research advancements in the pathogenesis of Parkinson’s disease – VJNeurology

  https://www.vjneurology.com/video/mnbvykpwjou-research-advancements-in-the-pathogenesis-of-parkinsons-disease/

  Serge Przedborski summarizes the research priorities in unraveling pathogenic mechanisms behind Parkinsons disease (PD). It is clear now that research into the pathogenesis of neurodegenerative diseases needs to consider multiple aspects, including multicellular levels and temporality. […] Therefore, a temporal and multicellular approach might be needed to improve our understanding of the disease pathogenesis and develop novel therapies. Currently, research focuses on two aspects: understanding why protein deposits are formed and how to prevent them and the development of technologies with temporal and cellular resolutions to obtain deep insight into the pathogenesis of PD.

• #127 New study puts gut microbiome at the center of Parkinson’s disease pathogenesis – UAB News

  https://www.uab.edu/news/research-innovation/new-study-puts-gut-microbiome-at-the-center-of-parkinson-s-disease-pathogenesis

  We anticipate that in the near future we will have the tools and the analytic power to use metagenomics as a new approach to study PD heterogeneity, search for biomarkers, delve deeper into the origin and progression of PD sub-phenotypes, and investigate the potential in manipulating the microbiome to prevent, treat and halt the progression of PD.

• #128 Pathogenesis of the Virome in Parkinson’s Disease | Parkinson’s Disease

  https://www.michaeljfox.org/grant/pathogenesis-virome-parkinsons-disease

  Numerous studies have implicated viruses as causal factors or potential triggers for Parkinsons disease (PD). […] Our central hypothesis is that virus variants, or yet unknown viruses, are able to reach the central nervous system and remain latent by hiding in neurons, thereby escaping detection from the immune system. Recurrent reactivation during aging triggers an immune and inflammatory reaction that can lead to PD in some individuals. […] This study may allow us to determine a possible association between neurotropic viruses and PD, which could provide innovative and impactful insight into PD pathogenesis and nominate potential treatment targets.

• #129 Pathogenesis of the Virome in Parkinson’s Disease | Parkinson’s Disease

  https://www.michaeljfox.org/grant/pathogenesis-virome-parkinsons-disease

  Numerous studies have implicated viruses as causal factors or potential triggers for Parkinsons disease (PD). […] Our central hypothesis is that virus variants, or yet unknown viruses, are able to reach the central nervous system and remain latent by hiding in neurons, thereby escaping detection from the immune system. Recurrent reactivation during aging triggers an immune and inflammatory reaction that can lead to PD in some individuals. […] This study may allow us to determine a possible association between neurotropic viruses and PD, which could provide innovative and impactful insight into PD pathogenesis and nominate potential treatment targets.

• #130 New study puts gut microbiome at the center of Parkinson’s disease pathogenesis – UAB News

  https://www.uab.edu/news/research-innovation/new-study-puts-gut-microbiome-at-the-center-of-parkinson-s-disease-pathogenesis

  We anticipate that in the near future we will have the tools and the analytic power to use metagenomics as a new approach to study PD heterogeneity, search for biomarkers, delve deeper into the origin and progression of PD sub-phenotypes, and investigate the potential in manipulating the microbiome to prevent, treat and halt the progression of PD.

• #131 ‘Parkinson’s is a man-made disease’: How a chemical Europe can’t quit may be driving the disease – POLITICO

  https://www.politico.eu/article/bas-bloem-parkinsons-pesticides-mptp-glyphosate-paraquat/

  The Netherlands, known for having one of the highest pesticide use rates in Europe, has seen a 30 percent rise in Parkinsons cases over the past decade a slower increase than in some other regions of the world, but still notable, Bloem says. […] To Bloem, reversing the epidemic means shifting the regulatory mindset from reaction to prevention. That means requiring long-term neurotoxicity studies, testing chemical combinations, accounting for real-world exposure, genetic predisposition and the kind of brain damage Parkinsons causes and critically, making manufacturers prove safety, rather than scientists having to prove harm.

• #132 The pathogenesis of Parkinson’s disease – PubMed

  https://pubmed.ncbi.nlm.nih.gov/38245249/

  Parkinson’s disease is a progressive neurodegenerative condition associated with the deposition of aggregated -synuclein. Insights into the pathogenesis of Parkinson’s disease have been derived from genetics and molecular pathology. […] Biochemical studies, investigation of transplanted neurons in patients with Parkinson’s disease, and cell and animal model studies suggest that abnormal aggregation of -synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson’s disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson’s disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson’s disease. Although there are currently no disease-modifying treatments for Parkinson’s disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.

• #133 Pathogenesis and current therapeutic approaches for Parkinson’s disease

  https://accscience.com/journal/GTM/3/4/10.36922/gtm.5082

  Parkinsons disease (PD) is a common neurodegenerative disorder among the elderly, characterized by a spectrum of motor and non-motor symptoms. […] Recent advancements in understanding the pathogenesis of PD have catalyzed the development of innovative treatment strategies. […] Emerging therapies, including gene therapy and stem cell therapy, offer transformative potential by addressing the underlying disease mechanisms. […] This review summarizes the latest research progress in the understanding of PD pathogenesis and treatment, aiming to provide guidance for the clinical management of PD.

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