Materiały źródłowe

• #1 Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5495055/

  Huntington’s disease is a late-onset neurodegenerative disease caused by a CAG trinucleotide repeat in the gene encoding the huntingtin protein. Despite its well-defined genetic origin, the molecular and cellular mechanisms underlying the disease are unclear and complex. […] The genetic basis of Huntingtons disease is well defined. However, the deleterious effects that arise from the abnormal protein are complex, and effective therapeutic interventions have yet to be identified. […] Despite the well-known genetic origin of HD, the number and variety of molecular alterations reported in HD is broad and not completely understood. Although it is known that toxicity in HD arises from a gain of function of the mutant protein, given that expression of an expanded polyglutamine is toxic itself, a contribution of a loss of function of the wild-type protein cannot be discarded because deletion or inactivation of wild-type huntingtin also leads to neurodegeneration.

• #2 Pathogenesis of Huntington’s Disease: An Emphasis on Molecular Pathways and Prevention by Natural Remedies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9599635/

  Huntingtons disease is an inherited autosomal dominant trait neuro-degenerative disorder caused by changes (mutations) of a gene called huntingtin (htt) that is located on the short arm (p) of chromosome 4, CAG expansion mutation. […] It is believed that the factors such as molecular genetics, oxidative stress, excitotoxicity, mitochondrial dysfunction, neuroglia dysfunction, protein aggregation, and altered UPS leads to HD. […] Degeneration of neurons in Huntingtons disease is distinguished by progressive loss of motor coordination and muscle function. This is due to the expansion of CAG trinucleotide in the first exon of the htt gene responsible for neuronal death and neuronal network degeneration in the brain. […] The biological pathways causing the disease are unknown and complicated, even though HD is distinguished by a well-defined genetic origin. Different mechanisms such as molecular genetics, leading to oxidative stress, metabolic dysfunction, and mitochondrial dysfunction, explain the pathological process of HD.

• #3 Huntington’s disease: MedlinePlus GeneticsLock

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

  Huntington’s disease is a progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition). […] Variants (also called mutations) in the HTT gene cause Huntington’s disease. The HTT gene provides instructions for making a protein called huntingtin. […] An increase in the size of the CAG segment leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington’s disease.

• #4 Huntington’s disease – Wikipedia

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

  Huntington’s disease (HD), also known as Huntington’s chorea, is an incurable neurodegenerative disease that is mostly inherited. […] The huntingtin gene provides the genetic information for huntingtin protein (Htt). Expansion of CAG repeats of cytosine-adenine-guanine (known as a trinucleotide repeat expansion) in the gene coding for the huntingtin protein results in an abnormal mutant protein (mHtt), which gradually damages brain cells through a number of possible mechanisms. […] The behavior of the mutated protein (mHtt) is not completely understood, but it is toxic to certain cell types, particularly brain cells. Early damage is most evident in the subcortical basal ganglia, initially in the striatum, but as the disease progresses, other areas of the brain are also affected, including regions of the cerebral cortex.

• #5 Factors That Contribute To Huntington’s Disease Pathogenesis | VectorLabs

  https://vectorlabs.com/blog/factors-that-contribute-to-huntingtons-disease-pathogenesis/?srsltid=AfmBOoqh1Q_7skJktvPSOflFF2fJs1sQ99mSSXVTolJCc6feK201v-8e

  Huntingtons disease (HD) develops due to a rare genetic mutation in the huntingtin gene (Htt), leading to progressive neurodegeneration in the cortex and striatum. Normal Htt contain about 18 CAG repeats, whereas mutated ones have 40 or more. The length of CAG repeat predicts the age of HD onset, but the length of polyQ repeats encoded by CAG and CAA is not as important to the overall HD pathogenesis. Once expressed, mutated huntingtin aggregates and triggers other neuropathological changes, including striatal-selective degeneration of medium spiny neurons (MSN), astrocytosis, and microgliosis. As a result, patients with HD develop motor dysfunction, cognitive impairment, and psychiatric symptoms. […] The new preclinical model developed by Gu et al. BAC-CAG is a BAC transgenic mouse model that expresses full-length human mutant huntingtin with about 120 uninterrupted CAG repeats. BAC-CAG mice showed morphological evidence of astrocytosis and microgliosis, other key hallmarks of human HD pathophysiology.

• #6 Huntington Disease – Neurologic Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/neurologic-disorders/movement-and-cerebellar-disorders/huntington-disease

  Huntington disease results from a mutation in the huntingtin (HTT) gene (on chromosome 4), causing abnormal repetition of the DNA sequence CAG, which codes for the amino acid glutamine. The resulting gene product, a large protein called huntingtin, has an expanded stretch of polyglutamine residues, which accumulate within neurons and lead to disease via unknown mechanisms. The more CAG repeats, the earlier the onset of disease and the more severe its expression (phenotype). The number of CAG repeats can increase with successive generations when the father transmits the mutation and, over time, can lead to increasingly severe phenotypes within a family (called anticipation). […] Therapies currently under study aim to reduce glutamatergic neurotransmission via the N-methyl-d-aspartate receptor and to bolster mitochondrial energy production. Treatments that aim to increase GABAergic function in the brain have been ineffective.

• #7 Huntington’s disease – Wikipedia

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

  The toxic action of mHtt may manifest and produce the HD pathology through multiple cellular changes. […] These protein fragments have a propensity to undergo misfolding and aggregation, yielding fibrillar aggregates in which non-native polyglutamine strands from multiple proteins are bonded together by hydrogen bonds. […] Mutant huntingtin protein has been found to play a key role in mitochondrial dysfunction. […] A somatic expansion of CAG repeats is involved in the progression of the disease. Over decades, the HTT gene first sees its CAG repeats expand to about 80 copies: the 35+ CAG locus causes additional slippage errors that expand the repeat. […] The area of the brain most damaged in early Huntington’s disease is the dorsal striatum made up of the caudate nucleus and the putamen.

• #8 Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities | Nature Reviews Neurology

  https://www.nature.com/articles/s41582-020-0389-4

  Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene (HTT) and involves a complex web of pathogenic mechanisms. […] Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. […] Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. […] Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. […] In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. […] Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit.

• #9 Huntington’s Disease: Complex Pathogenesis and Therapeutic Strategies

  https://www.mdpi.com/1422-0067/25/7/3845

  Huntington’s disease (HD) arises from the abnormal expansion of CAG repeats in the huntingtin gene (HTT), resulting in the production of the mutant huntingtin protein (mHTT) with a polyglutamine stretch in its N-terminus. The pathogenic mechanisms underlying HD are complex and not yet fully elucidated. However, mHTT forms aggregates and accumulates abnormally in neuronal nuclei and processes, leading to disruptions in multiple cellular functions. […] The underlying cause of HD is an abnormal expansion of CAG trinucleotide repeats in the HTT gene, where expanded CAGs code for polyglutamine stretch (polyQ). […] The exact mechanisms by which mHTT leads to neurodegeneration are still uncertain, but it is believed to involve a combination of toxic gain-of-function effects and loss of normal HTT function.

• #10 Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5495055/

  The hallmark of HD, and common to other polyglutamine disorders, is the presence of aggregates in the brain. These were initially considered crucial in HD pathology. […] Accumulation of pathogenic N-terminal fragments of huntingtin is characteristic in HD. These fragments come from diverse origins, including proteolysis by caspases, calpains, and other proteases. […] Transcriptional dysregulation has long been considered a major pathogenic mechanism in HD. DNA microarray studies have revealed that expression profiles of a number of genes are profoundly altered in HD. […] Gene expression dysregulation in HD might also arise from variations in the epigenetic landscape, as well as in the regulation of noncoding RNAs. […] Two major degradation pathways exist to degrade intracellular proteins: the ubiquitin-proteasome system (UPS), which efficiently degrades wild-type huntingtin, and the autophagy-lysosome system, which seems to be important in degrading the expanded mutant forms.

• #11 Huntington’s Disease: Complex Pathogenesis and Therapeutic Strategies

  https://www.mdpi.com/1422-0067/25/7/3845

  The aggregation of mHTT is a prominent pathological feature of HD. mHTT can spontaneously aggregate, forming various structures such as monomers, oligomers, and inclusion bodies composed of fibrils. […] The expanded polyQ region in HTT leads to an elongation of the random coil structure, further promoting protein aggregation. […] Large inclusion bodies containing mHTT were previously considered pathogenic. However, it is interesting to note that large mHTT inclusion bodies can occur without causing cell death, and conversely, cell death can occur without the presence of inclusion bodies. […] The abnormal N-terminal fragment and HTT exon1 protein can undergo misfolding and aggregation, leading to more severe cellular dysfunction and toxic effects. […] Understanding the cause of HD and its disease pathogenesis will aid in the development of treatment strategies.

• #12 Huntington Disease: Mechanism of Pathogenesis and Recent Developments in Its Therapeutic Strategies-A Short Review

  https://www.jchemrev.com/article_164822.html

  The toxic species in HD, on the other hand, have been recognized as decipherable repeating units of the misfolded protein, mHtt. […] Polyglutamine abnormal enlargement resulting in disease condition is due to a gain in function mechanism ascribed to a monogenic change in the CAG reiteration growth and HD is not an exception. […] The advance symptoms sometimes appear as a negligible physiological, cognitive, or emotive change. Many disorders seem to be much more dominant and possess a larger impact on the features and roles as the disease continues. […] The medical manifestation of HD carrier parent stands as one among the other diagnostic tools to detect possible individuals with HD through DNA analysis i.e. a double barrel approach of engaging clinical measures with genetics for examination.

• #13 Pathogenesis of Huntington’s Disease: An Emphasis on Molecular Pathways and Prevention by Natural Remedies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9599635/

  One of the major players in the pathogenic process of HD is attributed to transcriptional dysregulation. […] Mutant htt impairs transcription, according to DNA microarray studies. […] Dysregulation of CREB and Neuron restrictive silencer elements (NRSE) mediated transcription in HD and in normal person are described below. […] In HD individuals, mutant htt decline to interlink with REST-NRSF, resulting in elevated REST-NRSF levels in the nucleus. […] The stages involved in the UPS system failing and causing cellular pathogenesis in HD are listed below. […] Mitochondria serve as locations for oxidative phosphorylation and cellular respiration, both of which result in the production of ATP. […] A mitochondrial defect has been discovered in HD patients, which results in lower mitochondrial oxygen consumption, glucose metabolism, and cAMP levels in the cerebrospinal fluid.

• #14 Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation | IntechOpen

  https://www.intechopen.com/chapters/53820

  Htt functions in transcription are well established. Htt has been shown to interact with a large number of transcription factors, indicating a role of the protein in the control of gene transcription. […] The greatest number of downregulated genes in HD has led to the initiation of new lines of research aimed at testing the ability of a number of compounds to restore gene transcription in mouse models of HD. […] Mhtt establishes abnormal protein-protein interactions with several nuclear proteins and transcription factors, recruiting them into aggregates and inhibiting their activity. […] Mhtt can also fail to interact with other transcription factors, altering their activity which could induce the repression of a large cohort of neuronal-specific genes. […] Mhtt interaction with HATs inhibits proper histone acetylation and causes repression of the transcription.

• #15 Review of Huntington’s Disease: From Basics to Advances in Diagnosis and Treatment | Gonzalez Rojas | Journal of Neurology Research

  https://www.neurores.org/index.php/neurores/article/view/721/701

  Studies showed that the aggregates in adult-onset HD are typically cytoplasmic, while younger patients were more frequently located in the nucleus. These perinuclear aggregates proposed to be neurotoxic, causing cell death by abnormal activation of the cell cycle leading to apoptosis. […] In HD, oligomers of HTT protein sequestered chaperones, proteosome subunits, transcription factors and wild-type huntingtin (wHTT), weakening the protective capacity of the cell inducing a higher autophagy flux rate. […] A key molecular feature is the cleavage of huntingtin in the cytoplasm followed by the translocation of the fragments into the nucleus of striatal neurons. The accumulation of these fragments comes from proteolysis by caspases, calpains and other proteases. Although both types, wild and expanded, get cleaved, the presence of mutant fragments increases toxicity and has been proposed as the first step in the process of neurodegeneration. […] Several studies have demonstrated that expression profiles of a vast number of genes are deeply modified, mainly those related to neurotransmitter receptors and ion channels and brain-derived neurotrophic factor (BDNF), a pro-survival factor produced at the cortex which promotes striatal neurons survival.

• #16 Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5495055/

  Neuronal and synaptic abnormalities are early pathological events in HD. Neuronal homeostasis might be compromised not only by decreased transcription of essential genes in neurotransmission and signaling but also by defects in the delivery of proteins and organelles along their axons. […] Altered mitochondrial function resulting in defects in ATP production, Ca++ buffering capacity, and apoptosis is associated with neurodegeneration in HD. […] Emerging evidence suggests that prion-like transmission from cell to cell of proteins like tau or -synuclein spreads these disease-associated proteins to different brain regions. […] Although huntingtin aggregates are more prominent in neurons than in non-neuronal glial cells, glial cells also contribute to disease in HD, and reactive gliosis is observed in many HD mouse models and in postmortem brains of HD patients.

• #17 Huntington Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1150165-overview

  Data from striatal neuronal cultures transfected with mutant huntingtin and transgenic mice carrying the spinocerebellar ataxia-1 (SCA-1) gene (another CAG repeat disorder) suggest that NIIs may not be necessary or sufficient to cause neuronal cell death, but translocation into the nucleus is sufficient to cause neuronal cell death. […] The presence of neuronal intranuclear inclusions (NIIs) initially led to the view that they are toxic and, hence, pathogenic. […] The theory that reduced uptake of glutamate by glial cells may play a role in the pathogenesis of HD also has been proposed. […] Oxidative stress is caused by the presence of free radicals (ie, highly reactive oxygen derivatives) in large amounts. […] Impaired energy metabolism reduces the threshold for glutamate toxicity and can lead to activation of excitotoxic mechanisms as well as increased production of reactive oxygen species.

• #18 Review of Huntington’s Disease: From Basics to Advances in Diagnosis and Treatment | Gonzalez Rojas | Journal of Neurology Research

  https://www.neurores.org/index.php/neurores/article/view/721/701

  Synaptic abnormalities are premature pathological events in HD. HTT aggregates block axon transport, in addition to recruiting and annulling motor proteins, therefore inhibiting fast axonal transport. Loss of function of wHTT might be another point to consider, as in normal conditions, it enables vesicle transport. […] The cell machinery possesses many different mechanisms to dispose of abnormal proteins and organelles; for instance, the UPS, and the autophagy-lysosome system. […] HTT favors an increased entry of calcium inducing a failure at the respiratory chain. The final common pathway is a defective ATP production conducting the cell to apoptosis. […] Mitochondrial dysfunction is strongly implicated in the pathogenesis of HD. Therefore, several antioxidant compounds have shown promise as biomarker candidates, for example, decreased concentrations of glutathione peroxidase and copper-zinc superoxide dismutase in erythrocytes from HD patients compared with controls.

• #19 The regulatory roles of microRNAs toward pathogenesis and treatments in Huntington’s disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-021-00755-1

  In HD, over-expanded polyQ accelerates N-terminal mHTT fragments to transform to -sheet confirmations from -helical coiled coils, and easily leads to protein misfolding. […] These misfolded mHTTs disrupt gene regulation, vehicle trafficking, synaptic plasticity, protein clearance, neurogenesis, etc., and finally lead to cellular dysfunctions and death. […] Mitochondrial dysfunction is a common characteristic in different neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinsons disease (PD) and Spinocerebellar Ataxia, and failure of mitochondrial functions results in increases of oxidative stress and deficits of energy production, further leading to neurodegenerations. […] In HD, mHTT has been reported to be degraded slowly, and impairment of two protein degradation systems has been found in different HD models.

• #20 From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research

  https://www.mdpi.com/1422-0067/24/16/13021

  Toxic mutant huntingtin oligomer species interfere with ER-associated degradation components (ERAD) resulting in ER stress and the activation of the unfolded protein response. […] Mutant huntingtin has been shown to stimulate the formation of autophagosomes through the inactivation of the mTOR kinase pathway. However, despite the increase in autophagosome formation, cargo loading into autophagosomes is impaired in HD.

• #21 The regulatory roles of microRNAs toward pathogenesis and treatments in Huntington’s disease | Journal of Biomedical Science | Full Text

  https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-021-00755-1

  As a result, enhancement of these two protein degradation systems is also considered as a potential strategy of therapy in HD. […] Since the HD is a monogenetic disease, mHTT-lowering strategy is considered as a potential direction for the therapy. […] In addition to targeting on mHTT, increases of neuroprotective effects through other functional genes, such as neurotrophic factors, growth factors, anti-oxidative stress genes and microRNAs, have also alleviated HD symptoms. […] The expression profiling of miRNAs in HD patients has been reported in several studies, and altered miRNAs are highly associated with the regulation of molecular or pathological phenotypes. […] As a result, miRNAs are recently addressed as biomarkers to indicate the progression of HD in clinic. […] Overall, since these in vivo data show strong evidence to alleviate HD progression in animal models, it highly raises this potential therapy using miRNA-based strategies in HD.

• #22 From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research

  https://www.mdpi.com/1422-0067/24/16/13021

  An assortment of mechanisms for HD pathogenesis have been proposed and investigated. Two core hypotheses constitute the rationale for research and therapeutic design: a gain of aberrant toxicity from mHTT expression and a dominant loss of normal activity from wild-type HTT as a result of mHTT expression. […] Glutamate excitotoxicity as an initiator of neuronal death has been a longstanding hypothesis and research focus in neurodegenerative disorders. […] In HD, it has been proposed that the neurodegeneration of the medium spiny neurons of the striatum is caused by excess glutamate in the synapses resulting from a lack of synaptic glutamate clearance and an increased glutamate release. […] Evidence for mitochondrial dysfunction in HD stems from the observation that systemic administration of 3-nitropropionic acid, an irreversible inhibitor of complex II of the mitochondrial electron transport chain in both rodents and non-human primates, reproduced many of the behavioural and anatomical characteristics of HD.

• #23 Pathogenesis of Huntington’s Disease: How to Fight Excitotoxicity and Transcriptional Dysregulation | IntechOpen

  https://www.intechopen.com/chapters/53820

  Ultimately, excitotoxicity contributes to neuronal degeneration in many acute as well as chronic central nervous system diseases. […] Polyglutamine expansion produces a hyperactivation of N-methyl-D-aspartate receptor (NMDAR and kainite receptors); stabilizes NMDA receptors in the postsynaptic membrane; inhibits the uptake and release of glutamate at the synapses; and can also sensitize the inositol (1,4,5)-triphosphate receptor type 1 located in the membrane of the endoplasmatic reticulum. […] In addition, mhtt can contribute to excitotoxicity by decreasing the expression of the major astroglial glutamate transporter (GLT-1), which reduces the glutamate uptake.

• #24 A Pathogenic Mechanism in Huntington’s Disease Involves Small CAG-Repeated RNAs with Neurotoxic Activity | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002481

  Huntington’s disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. […] Here we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of 21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism.

• #25 A Pathogenic Mechanism in Huntington’s Disease Involves Small CAG-Repeated RNAs with Neurotoxic Activity | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002481

  These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches. […] Here we provide evidence for a pathogenic role of the mutant HTT RNA. CAG-expanded HTT RNA can be processed to generate CAG-repeated short RNAs with neurotoxic activity. We show that expanded HTT toxic effect is dependent on RNA-induced silencing complex (RISC) and further demonstrate that expanded HTT participates in posttranscriptional gene silencing of genes containing pure and interrupted CTG repeats. This, together with HTT polyglutamine toxicity, may contribute to the neurodegeneration pattern observed in HD.

• #26 A Pathogenic Mechanism in Huntington’s Disease Involves Small CAG-Repeated RNAs with Neurotoxic Activity | PLOS Genetics

  https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1002481

  The toxic effect of the sRNA fraction generated by expanded HTT is dependent on Ago proteins and is abolished by anti-sCAG. Furthermore, increased levels of sCAGs were found in Ago2 immunoprecipitates of cells expressing expanded HTT-e1, suggesting that sCAG-driven gene silencing may underlie HTT-RNA toxicity. […] In summary, we propose a pathogenic RNA dependent mechanism in HD by which sCAG produced over a threshold are neurotoxic. In HD, this mechanism may complement other RNA dependent processes including miRNA deregulation and possible alterations in alternative splicing driven by MBNL1 sequestration.

• #27 Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities | Nature Reviews Neurology

  https://www.nature.com/articles/s41582-020-0389-4

  Nucleocytoplasmic transport is disrupted in HD by sequestration of nuclear pore components in HTT aggregates; modulation of nucleocytoplasmic transport is neuroprotective and might provide a novel therapeutic opportunity. […] Changes in cerebrospinal fluid and serum biomarkers, including neurofilament light chain and mutant HTT, are among the earliest detectable changes in HD and can predict disease onset and track progression. […] Intrathecally delivered non-allele-selective antisense oligonucleotides (ASOs) have successfully lowered HTT concentrations in the central nervous system of individuals with HD, and trials of allele-specific ASOs are under way. […] Gene-editing strategies for HTT lowering, including zinc finger proteins, transcription activator-like effector nucleases and CRISPRCas9, are currently in preclinical development, but need to be delivered via the injection of viral vectors, which can be challenging.

• #28 Multiple pathways contribute to the pathogenesis of Huntington disease | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-1-19

  Huntington disease (HD) is caused by expansion of a polyglutamine (polyQ) domain in the protein known as huntingtin (htt), and the disease is characterized by selective neurodegeneration. […] The widespread expression and localization of mutant htt and its interactions with a variety of proteins suggest that mutant htt engages multiple pathogenic pathways. Understanding these pathways will help us to elucidate the pathogenesis of HD and to target therapies effectively. […] The essential role of htt has been established using HD gene knockout mice. In this model, the absence of htt causes cell degeneration and embryonic lethality. […] However, there is more evidence to support the theory wherein mutant htt gains a toxic function. […] Despite its widespread distribution, mutant htt causes selective neurodegeneration, which occurs preferentially and most prominently in the striatum and deeper layers of the cortex in the early stages of HD.

• #29 Huntington Disease: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1150165-overview

  Huntington disease (HD) is an incurable, adult-onset, autosomal dominant inherited disorder associated with cell loss within a specific subset of neurons in the basal ganglia and cortex. […] The most striking neuropathology in Huntington disease (HD) occurs within the neostriatum, in which gross atrophy of the caudate nucleus and putamen is accompanied by selective neuronal loss and astrogliosis. […] The genetic basis of HD is the expansion of a cysteine-adenosine-guanine (CAG) repeat encoding a polyglutamine tract in the N-terminus of the protein product called huntingtin. […] The function of huntingtin is not known. […] N-terminal fragments of mutant huntingtin accumulate and form inclusions in the cell nucleus in the brains of patients with HD, as well as in various animal and cell models of HD.

• #30 Pathogenesis of Huntington’s Disease: An Emphasis on Molecular Pathways and Prevention by Natural Remedies

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9599635/

  Htt is known to be much more abundant in neurons as compared to non-neuronal glial cells. […] Glial cells are majorly responsible for HD progression and pathogenesis. […] The secretion of pro-inflammatory cytokines by astrocytes is associated with neuroinflammation and neurodegeneration in HD. […] Axonal transport is necessary for appropriate transfer to neuronal membranes in order to facilitate synaptic communication. […] In HD, MSNs in the striatum show the most noticeable deterioration. […] The integration of motor, emotional, autonomic, and cognitive responses to pain are one of the fundamental functions of the basal ganglia in the processing and analgesia of pain. […] The neuroprotective effect of natural products in HD experimental models has been extensively studied. Indeed, based on relevant studies, natural products offer neuroprotection in experimental models predominantly through the antioxidant defense system, scavenging free radicals, neutralization of reactive oxygen species (ROS), reduction of oxidative stress, preservation of mitochondrial function, anti-inflammatory protection, inhibition of apoptosis, and induction of autophagy.

• #31 From Pathogenesis to Therapeutics: A Review of 150 Years of Huntington’s Disease Research

  https://www.mdpi.com/1422-0067/24/16/13021

  The genetic aetiology was defined as an expansion of a polyglutamine coding repeat in exon 1 of the huntingtin gene, which leads to the development of an accurate genetic test for diagnosis. […] The underlying molecular pathogenesis leading to the macroscopic neuronal loss remains to be comprehensively explained, and therapies in current clinical use were selected to alleviate symptoms rather than to delay or prevent the onset of the condition. […] Neuropathologically, it is well established that the basal ganglia, particularly the medium spiny neurons of the striatum, are the most affected tissue in HD. […] The death of GABAergic medium spiny neurons (MSN) located in the striatum and projecting into the globus pallidus externa is a hallmark of HD. […] The preferential susceptibility of MSN degeneration is debated, although prevailing hypotheses include the observation of increased somatic instability in the striatum compared with other brain regions, preferential glutamate excitotoxicity of MSN, vulnerability for mitochondrial dysfunction due to an increased metabolic demand in MSNs, and altered striatal brain-derived neurotrophic factor (BDNF) activity.

• #32 Presymptomatic Targeted Circuit Manipulation for Ameliorating Huntington’s Disease Pathogenesis | bioRxiv

  https://www.biorxiv.org/content/10.1101/2024.07.24.604946v1.full

  Early stages of Huntington’s disease (HD) before the onset of motor and cognitive symptoms are characterized by imbalanced excitatory and inhibitory output from the cortex to striatal and subcortical structures. […] The loss of iSPNs disrupts the indirect pathway responsible for repressing globus pallidus external (GPe) neuronal activity. Consequently, this imbalance tilts the network towards continuous and involuntary excitatory states, underlying the hyperactive motor symptoms in early HD stages. […] Studies in rodent HD models during pre- and early symptomatic stages have revealed intricate alterations in intrinsic and synaptic properties of affected neurons. […] However, there are currently no effective therapies targeting HD’s underlying pathophysiology. […] Addressing the excitatory and inhibitory imbalance in early HD stages could mitigate a range of symptoms spanning mental health, behavior, movement, and communication.

• #33 Huntington’s disease – Wikipedia

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

  Initially, damage to the brain is regionally specific with the dorsal striatum in the subcortical basal ganglia being primarily affected, followed later by cortical involvement in all areas. […] The accumulating damage to this area causes the characteristic erratic movements associated with HD known as chorea, a dyskinesia.

• #34 Study finds surprising way that genetic mutation causes Huntington’s disease, transforming understanding of the disorder | Broad Institute

  https://www.broadinstitute.org/news/study-finds-surprising-way-genetic-mutation-causes-huntingtons-disease-transforming

  Researchers studying brain cells from Huntingtons patients show that the mutation, which changes over decades, becomes toxic only later in life. Scientists at the Broad Institute of MIT and Harvard, Harvard Medical School, and McLean Hospital have discovered a surprising mechanism by which the inherited genetic mutation known to cause Huntingtons disease leads to the death of brain cells. A new study published today in Cell reveals that the inherited mutation doesnt itself harm cells. Rather, the mutation is innocuous for decades but slowly morphs into a highly toxic form that then quickly kills the cell. The Huntingtons mutation involves a stretch of DNA in the HTT gene in which a three-letter sequence of DNA, CAG, is repeated at least 40 times, as opposed to the 15-35 repeats inherited by people without the disease. Only once a cell’s DNA expansion reaches a threshold number of CAGs roughly 150 does the cell sicken and then die. The cumulative death of many such cells leads to the symptoms of Huntingtons disease. The study offers a potential explanation as to why candidate Huntingtons drugs that aim to reduce expression of the HTT protein have struggled in clinical trials: Very few cells have the toxic version of the protein at any given time, so the treatments may not be having a therapeutic effect in most cells. The research also elevates a different therapeutic strategy: Stopping or slowing the CAG-repeat expansion in the HTT gene might postpone toxicity in a far larger number of cells, delaying or even preventing the onset of the disease. McCarrolls team suggests that rather than targeting the HTT protein, a complementary or potentially better therapeutic approach could be to slow or stop the DNA-repeat expansion, which could help delay or even prevent the disease. Most surprisingly, the research team found that expansion of the DNA repeat from 40 to 150 CAGs had no apparent effect on the neurons’ health. But neurons whose repeats exceeded 150 CAGs showed greatly distorted gene expression, losing expression of critical genes and then dying. This means that a neuron spends more than 95 percent of its life with an innocuous HTT gene. Moreover, because the CAG-repeat tracts in different cells cross this toxicity threshold at different times, the cells, as a group, disappear slowly over a long period, starting about 20 years before symptoms appear and more quickly as symptoms commence.

• #35 Discovery of key mechanism in Huntington’s disease could pave the way for early detection and treatment

  https://medicalxpress.com/news/2024-10-discovery-key-mechanism-huntington-disease.html

  Researchers from the University of Oxford have identified a key biochemical mechanism relevant to the development of Huntington’s disease. This discovery opens up the possibility of studying the disease before its clinical onset and eventually stopping its progression. […] The study, published in Nature Metabolism, has shown for the first time the biochemical change responsible for the development of Huntington’s disease, and how blocking this change stopped disease progression. […] The researchers identified that problems with specific neurons in the brain, called indirect pathway spiny projection neurons (iSPNs), which are the initially affected cells in HD, may trigger an imbalance in dopamine levels upon missing an important signaling derived from the activation of the neurotrophin receptor TrkB. This imbalance is linked to early symptoms of the disease, such as abnormal, involuntary movements.

• #36 Discovery of key mechanism in Huntington’s disease could pave the way for early detection and treatment

  https://medicalxpress.com/news/2024-10-discovery-key-mechanism-huntington-disease.html

  First, the researchers looked at mice that lacked normal function in these iSPNs due to disrupted TrkB neurotrophin signaling and noticed that they showed increased levels of dopamine in the brain, leading to hyperactivity. This change occurred before noticeable symptoms appeared, suggesting that these early alterations may contribute significantly to HD progression. […] The researchers also found that a protein called GSTO2, an enzyme that is part of the glutathione metabolism, plays an important role in regulating dopamine levels. By selectively reducing the activity of this protein in mice, the researchers were able to prevent dopamine and energy metabolism dysfunction, arresting the onset of motor symptoms in mice. […] Importantly, this enzyme shows similar dysregulation in a rat model of HD and some rare brains of asymptomatic HD patients, confirming its putative relevance to the development of the disorder.

• #37 Discovery of key mechanism in Huntington’s disease could pave the way for early detection and treatment

  https://medicalxpress.com/news/2024-10-discovery-key-mechanism-huntington-disease.html

  „This research marks the first time that we have been able to identify a specific chemical change that is unique to the development of Huntington’s disease, which opens the possibility of developing new tests to study the early changes of the disease before irreversible damage occurs. […] „Understanding these early changes provides crucial insights into how Huntington’s Disease develops, and this knowledge could help develop preventive therapies to maintain dopamine balance and delay or halt disease progression.” […] „Despite our significant understanding of its pathophysiology, HD remains without a cure, which underscores the necessity of delivering diagnostic and therapeutic interventions prior to the onset of symptoms, and this study is a step in that direction.”

• #38 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20250108/Researchers-uncover-molecular-mechanisms-driving-RNA-processing-defects-in-Huntingtons-disease.aspx

  A University of California, Irvine-led research team has discovered intricate molecular mechanisms driving the RNA processing defects that lead to Huntington’s disease and link HD with other neurodegenerative disorders such as amyotrophic lateral sclerosis, frontotemporal lobar dementia and Alzheimer’s disease. […] While it’s known that HD is caused by an abnormal expansion of cytosine, adenine and guanine nucleotide repeats in the DNA of the gene responsible for HD, how this mutation interferes with cellular functions is highly complex. […] The study, recently published online in the journal Nature Neuroscience, reveals the interplay between two key regulators of RNA processing. Binding of both the RNA-binding protein TDP-43 and the m6A RNA modification chemical tag has been found to be altered on genes that are dysregulated in HD.

• #39 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20250108/Researchers-uncover-molecular-mechanisms-driving-RNA-processing-defects-in-Huntingtons-disease.aspx

  „Our findings offer new insights into the role of TDP-43 and m6A modifications in contributing to defective RNA processing in HD. This enhanced understanding highlights their potential as therapeutic targets, which are major areas of research for other neurological disorders. […] The researchers discovered that in both HD mouse models and human patients, the mislocalization of TDP-43 and alterations in m6A RNA modifications disrupt TDP-43’s ability to bind to RNA correctly. This disruption leads to abnormal RNA processing and splicing errors. […] By targeting key processes like RNA splicing and modification, we not only advance our understanding of the molecular disruptions behind HD but also open the door to potential new treatments for neurodegenerative diseases more broadly.

• #40 Understanding Huntington’s Disease pathogenesis using next generation sequencing analyses

  https://dspace.mit.edu/handle/1721.1/103260

  Analysis of RNA-Seq results for splicing changes showed that mutant HTT itself is mis-spliced. This mis-splicing product is translated into a small, pathogenic HTT fragment which may have considerable implications for HD therapeutic design. […] Thus RNASeq data on muscle tissue from mouse models of several CAG expansion disorders was examined for genome-wide splicing alterations. Widespread mis-splicing was detected in the muscle of both Spinocerebellar ataxia 7 and Huntington’s disease mouse models and minor splicing dysregulation was detected in Spinal-bulbar muscular atrophy. […] Concurrent Ribo-Seq and RNA-Seq in diseased and wildtype animals would answer if there was altered translational control.

• #41 Presymptomatic Targeted Circuit Manipulation for Ameliorating Huntington’s Disease Pathogenesis | bioRxiv

  https://www.biorxiv.org/content/10.1101/2024.07.24.604946v1.full

  Our study aimed to normalize E/I imbalance via cell-type-specific modulation to impede HD progression in mice using Bioluminescent Optogenetics (BL-OG). […] The results demonstrate that either the inhibition of cortical pyramidal neurons or excitation of inhibitory parvalbumin interneurons in M1 cortex does improve motor coordination on the rotarod and inter-limb gait performance on the CatWalk in R6/2 mice. […] Taken together, the data generated from this study reveals that bioluminescent-driven optogenetic modulation of neuronal activities before the onset of symptoms attenuates Huntington’s disease motoric phenotypes.

• #42 Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities | Nature Reviews Neurology

  https://www.nature.com/articles/s41582-020-0389-4

  Therapeutically, the first human trial of an HTT-lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. […] A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. […] In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself. […] Proteins involved in DNA repair, particularly mismatch repair, can modify the age at onset and rate of progression of Huntington disease (HD), probably by altering the rate of somatic expansion of CAG repeats in the huntingtin gene (HTT). […] The modulation of DNA repair factors, such as MSH3, FAN1, PMS2 and LIG1, has therapeutic potential in HD and other repeat expansion diseases.

• #43 Huntington’s disease: Molecular basis of pathology and status of current therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2016.3566

  Considering that selective modulation of phosphorylation of serine residues can be exploited to modulate mutHTT activity, small molecule kinase inhibitors are being tested, even though their selectivity is being investigated. […] Another important HD pathology-associated change is in the cyclic AMP (cAMP) signaling and aberrant transcription of genes regulated by the cAMP response element. […] Reducing the content of mutHTT by inhibiting gene transcription, mRNA translation or promoting the breakdown of mRNA coding for HTT, may reduce any associated downstream damaging effects of mutHTT, which otherwise lead to the pathogenesis of HD. […] Inhibition of transcription by zinc finger proteins (ZFPs) were used to reduce the transcription from the HTT gene. […] Another approach to lower the expression of mutHTT is to target the corresponding mRNA with specific antisense oligonucleotides (ASOs), which are single-stranded DNA oligonucleotides, and bind to complimentary mRNA sequences via base-pairing and lead to the degradation of the mRNA by RNAse H.

• #44 Huntington’s disease: Molecular basis of pathology and status of current therapeutic approaches (Review)

  https://www.spandidos-publications.com/10.3892/etm.2016.3566

  Recent advancements in gene silencing efficiency as well as sustained long-term effects of RNAi agents have overtaken the ZFPs and ASOs, despite their therapeutic potential. […] In addition to the abovementioned approaches, stem cell-based therapies, in particular, using the patient-specific iPSCs are being developed and are promising to combat HD. […] Therapeutic strategies addressing a reduction in the mutHTT content at the genome, mRNA or protein degradation level and post-tranlational modification of mutHTT are being studied in preclinical models and in clinical trials.

• #45 Researchers identify a new mechanism that may halt Huntington’s disease progression

  https://frontlinegenomics.com/researchers-identify-a-new-mechanism-that-may-halt-huntingtons-disease-progression/

  Huntington’s disease (HD) is a progressive neurodegenerative disorder that causes changes to the brain, which ultimately alter a patient’s movement, mood, and cognitive ability. […] These changes are caused by an increase in toxic repetitive nucleotide sequences in the huntingtin gene (HTT). The repetition of CAG sequences increases over time due to the malfunction of cellular machinery that promotes DNA repair. This phenomenon is known as DNA mismatch repair. The overuse of DNA mismatch repair drives the onset and progression of HD. […] The results showed that FAN1 binds to MHL1 to block the accumulation of protein after DNA mismatch repair and protect against CAG repeat expansion. This process in turn can alleviate the toxicity that is found in the cells of patients with HD.

• #46 Research reveals new understanding of Huntington’s disease mechanism – The Daily Cardinal

  https://www.dailycardinal.com/article/2024/07/research-reveals-new-understanding-of-huntingtons-disease-mechanism

  A new preprint authored by Robert Hansaker, recently released on May 20 from the Broad Institute of MIT and Harvard found the number of repeats not to be the cause of HD and disputed the idea of cumulative cell damage. […] This tells us something interesting: instead of the problem being the amount of CAG repeats someone inherited, the problem is that the DNA replication mechanism is malfunctioning. This malfunction creates additional repeats over many years. Once you reach the threshold, there is acute degradation within the cells, which causes motor function and cognitive decline. […] The preprint noted that there is a possibility for intervention to slow down and postpone HD symptom onset. This could be done using therapies that target the mechanisms responsible for the increase in CAG repeats.

• #47 Discovery of a potent small molecule inhibiting Huntington’s disease (HD) pathogenesis via targeting CAG repeats RNA and Poly Q protein | Scientific Reports

  https://www.nature.com/articles/s41598-019-53410-z

  CAG repeats RNA causes various fatal neurodegenerative diseases exemplified by Huntingtons disease (HD) and several spinocerebellar ataxias (SCAs). […] The shared cause of these diseases raises the possibility for the exploiting the common target as a potential therapeutic approach. […] Here, we have used the chemical similarity search approach to discern the small molecules that selectively target toxic CAG RNA. […] Furthermore, the lead compounds also explicitly alleviate the polyQ mediated toxicity in HD cell models and patient-derived cells. […] These findings suggest that the lead compound could act as a chemical probe for AA mismatch containing RNA as well as plays a neuroprotective role in fatal neurodegenerative diseases like HD and SCAs. […] CAG repeats expansion translates into polyglutamine which further forms the polyQ aggregates, a crucial pathological hallmark of HD patients.

• #48 Discovery of a potent small molecule inhibiting Huntington’s disease (HD) pathogenesis via targeting CAG repeats RNA and Poly Q protein | Scientific Reports

  https://www.nature.com/articles/s41598-019-53410-z

  The rationally designed small molecules for this toxic 5CAG/3GAC RNA could provide a valuable avenue as a therapeutic approach for these Trinucleotide repeat expansion diseases. […] Therefore, we have used chemical similarity search to explore new potent small molecules that could be utilized to target the pathogenic CAG repeats, causing HD and SCAs. […] The most potent conformer of CP2, CP6, and CP13 compounds bind with RNA with the binding energy of 6.76, 6.84 and 7.43kcal/mole, respectively. […] However, the validation of reducing the CAG RNA and poly Q mediated toxicity is prerequisite for the therapeutic approaches, and therefore we have further validated our compounds in HD and SCA cellular models to assess the efficacy of these compounds. […] Polyglutamine disorders are a type of neurodegenerative disorders, which are characterized by an abnormal expansion of trinucleotide CAG repeat, which codes for glutamine amino acid.

• #49 Brain’s Own Repair Mechanism: New Neurons May Reverse Damage in Huntington’s Disease | URMC Newsroom

  https://www.urmc.rochester.edu/news/story/brains-own-repair-mechanism-new-neurons-may-reverse-damage-in-huntingtons-disease

  New research shows that the adult brain can generate new neurons that integrate into key motor circuits. […] This discovery offers a potential new way to restore brain function and slow the progression of these diseases. […] The idea that the adult brain retains the capacity to produce new neurons, called adult neurogenesis, was first described by Goldman and others in the 1980s while studying neuroplasticity in canaries. […] Further research in Goldmans lab showed that new neurons were generated when BDNF and another protein, Noggin, were delivered to progenitor cells in the brains of mice. […] The new research, conducted in a mouse model of Huntingtons disease, demonstrates that the newly generated neurons connect with the complex networks in the brain responsible for motor control, replacing the function of the neurons lost in Huntingtons.

• #50 Brain’s Own Repair Mechanism: New Neurons May Reverse Damage in Huntington’s Disease | URMC Newsroom

  https://www.urmc.rochester.edu/news/story/brains-own-repair-mechanism-new-neurons-may-reverse-damage-in-huntingtons-disease

  The study indicates that a possible treatment for Huntingtons disease would be to encourage the brain to replace lost cells with new, functional ones and restore the brains communication pathways. […] These findings suggest the potential for this regenerative approach as a treatment strategy in Huntingtons and other disorders characterized by the loss of neurons in the striatum. […] Research in Goldmans lab has shown that glial cells called astrocytes also play an important role in Huntingtons disease.

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