Materiały źródłowe

• #1 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  Multiple System Atrophy (MSA) is a severe neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia, dysautonomia and other motor and non-motor symptoms. […] Although several efforts have been dedicated to understanding the causative mechanisms of the disease, MSA pathogenesis remains widely unknown. […] The aim of the present review is to describe the state of the art about MSA pathogenesis, with a particular focus on alpha-synuclein accumulation and mitochondrial dysfunction, and to highlight future possible perspectives in this field. […] Overall, the present review provides a comprehensive and up-to-date overview of the mechanisms underlying MSA pathogenesis. […] Although the cause of MSA is still obscure, a relevant effort has been dedicated to understanding the pathogenic mechanisms.

• #2 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives – PubMed

  https://pubmed.ncbi.nlm.nih.gov/31300049/

  Multiple System Atrophy (MSA) is a severe neurodegenerative disease clinically characterized by parkinsonism, cerebellar ataxia, dysautonomia and other motor and non-motor symptoms. […] Although several efforts have been dedicated to understanding the causative mechanisms of the disease, MSA pathogenesis remains widely unknown. […] The aim of the present review is to describe the state of the art about MSA pathogenesis, with a particular focus on alpha-synuclein accumulation and mitochondrial dysfunction, and to highlight future possible perspectives in this field. […] In particular, this review describes the most widely investigated hypotheses explaining alpha-synuclein accumulation in oligodendrocytes, including SNCA expression, neuron-oligodendrocyte protein transfer, impaired protein degradation and alpha-synuclein spread mechanisms.

• #3 Multiple system atrophy: Epidemiology, pathology, and pathogenesis – UpToDate

  https://www.uptodate.com/contents/multiple-system-atrophy-epidemiology-pathology-and-pathogenesis

  Multiple system atrophy (MSA) is a rare neurodegenerative disorder that pathologically involves the basal ganglia, brainstem, cerebellum, and spinal cord; it clinically presents with various combinations of autonomic dysfunction, parkinsonism, ataxia, and corticospinal degeneration. […] MSA is one of several neurodegenerative disorders associated with alpha-synuclein aggregation, or synucleinopathies; others include Parkinson disease (PD) and dementia with Lewy bodies (DLB). […] This topic will review the epidemiology, pathology, pathogenesis, and genetics of MSA.

• #4 Multiple system atrophy – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/multiple-system-atrophy/symptoms-causes/syc-20356153

  There is no known cause for multiple system atrophy (MSA). Some researchers are studying the possible role of genetics or environmental causes such as a toxin in MSA. But there’s no substantial evidence to support these theories. […] MSA causes parts of the brain to shrink. This is known as atrophy. The areas of the brain that shrink due to MSA include the cerebellum, basal ganglia and brainstem. The atrophy of these parts of the brain affect internal body functions and movement. […] Under a microscope, the brain tissue of people with MSA shows a buildup of a protein called alpha-synuclein. Some research suggests that the buildup of this protein leads to multiple system atrophy.

• #5 Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-020-0185-5

  Multiple system atrophy (MSA) is a debilitating and fatal neurodegenerative disorder. The disease pathogenesis is still enigmatic. Neurodegeneration in MSA brains is preceded by the emergence of glial cytoplasmic inclusions (GCIs), which are insoluble -synuclein accumulations within oligodendrocytes (OLGs). The primary pathogenesis of GCIs may involve myelin dysfunction and dyshomeostasis of the oligodendroglial cellular environment such as autophagy and iron metabolism. We have previously reported that oligodendrocyte precursor cells are more prone to develop intracellular inclusions in the presence of extracellular fibrillary -synuclein. This finding implies a possibility that the propagation of GCI pathology in MSA brains is mediated through the internalization of pathological -synuclein into oligodendrocyte precursor cells. The interaction between glial cells and -synuclein is also highlighted with previous studies of post-mortem human brains, cultured cells, and animal models, which provide comprehensive insight into GCIs and the MSA pathomechanisms.

• #6 Multiple system atrophy – Wikipedia

  https://en.wikipedia.org/wiki/Multiple_system_atrophy

  Multiple system atrophy can be explained as cell loss and gliosis or a proliferation of astrocytes in damaged areas of the central nervous system. […] The presence of inclusion bodies known as Papp-Lantos bodies, in the movement, balance, and autonomic-control centres of the brain are the defining histopathologic hallmark of MSA. […] The major filamentous component of Papp-Lantos bodies, glial and neuronal cytoplasmic inclusions, is alpha-synuclein. […] Mutations in this substance may play a role in the disease. […] The conformation of the alpha-synuclein is different from that of alpha-synuclein in Lewy bodies. […] The disease probably starts with an oligodendrogliopathy. […] It has been proposed that the -synuclein inclusions found in Oligodendrocytes result from the pruning and the engulfment of diseased axonal segments containing aggregated -synuclein, i.e., of Lewy neurites. […] Tau proteins have been found in some glial cytoplasmic inclusion bodies.

• #7 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  This review focuses on alpha-syn accumulation, which is by far the most widely investigated mechanism, and mitochondrial dysfunction, whose analysis has provided relevant advances in recent years. […] Several hypotheses have been proposed to explain the aberrant localization of alpha-syn in MSA. […] The first hypothesis is that a reactivation of alpha-syn gene (SNCA) transcription occurs in the disease. […] The hypothesis of an aberrant SNCA expression in MSA oligodendroglia is intriguing, but the conflicting available data do not allow one to draw definite conclusions about this issue. […] A second hypothesis about the mechanisms leading to alpha-syn accumulation in MSA suggests that the protein is not produced directly in oligodendroglia, but that it is taken-up from neurons or from the extracellular environment.

• #8 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  This review focuses on alpha-syn accumulation, which is by far the most widely investigated mechanism, and mitochondrial dysfunction, whose analysis has provided relevant advances in recent years. […] Several hypotheses have been proposed to explain the aberrant localization of alpha-syn in MSA. […] The first hypothesis is that a reactivation of alpha-syn gene (SNCA) transcription occurs in the disease. […] The hypothesis of an aberrant SNCA expression in MSA oligodendroglia is intriguing, but the conflicting available data do not allow one to draw definite conclusions about this issue. […] A second hypothesis about the mechanisms leading to alpha-syn accumulation in MSA suggests that the protein is not produced directly in oligodendroglia, but that it is taken-up from neurons or from the extracellular environment.

• #9 Models of multiple system atrophy | Experimental & Molecular Medicine

  https://www.nature.com/articles/s12276-019-0346-8

  A study by Peng et al. showed differences between GCI–synuclein and LB–synuclein. These inclusions are conformationally and biologically distinct. GCI–synuclein is 1000-fold more potent than LB–synuclein in seeding the aggregation of monomeric -synuclein, which may explain the highly aggressive and rapidly progressive nature of MSA symptoms. […] The mechanisms of the accumulation of -synuclein in oligodendrocytes are still unknown. Several hypotheses have provided possible explanations as to how GCIs form. One possibility is that they form through the induced expression and aggregation of -synuclein in oligodendrocytes and other glial cells under disease conditions, but there is little evidence to support this cell-autonomous mechanism. An alternative explanation is that they form through the uptake of -synuclein secreted from neurons by oligodendrocytes.

• #10 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  This review focuses on alpha-syn accumulation, which is by far the most widely investigated mechanism, and mitochondrial dysfunction, whose analysis has provided relevant advances in recent years. […] Several hypotheses have been proposed to explain the aberrant localization of alpha-syn in MSA. […] The first hypothesis is that a reactivation of alpha-syn gene (SNCA) transcription occurs in the disease. […] The hypothesis of an aberrant SNCA expression in MSA oligodendroglia is intriguing, but the conflicting available data do not allow one to draw definite conclusions about this issue. […] A second hypothesis about the mechanisms leading to alpha-syn accumulation in MSA suggests that the protein is not produced directly in oligodendroglia, but that it is taken-up from neurons or from the extracellular environment.

• #11 The neuropathology of multiple system atrophy and its therapeutic implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5954415/

  Given the high levels and widespread distribution of -syn aggregates in MSA, it is possible that both propagation and oligodendroglial -syn expression might be occurring simultaneously. […] Supporting the possibility of propagation, several studies have shown that -syn aggregates can transmit from neuron to neuron, neuron to astroglial and oligodendroglial cells, and oligodendroglial to astroglial cells, leading to neuronal dysfunction, apoptosis and neuroinflammation. […] Moreover, recent studies have shown that injection of homogenates from MSA brains propagate -syn pathology in a prion-like fashion in the murine brain. […] Whether its origin is intracellular or due to cell-to-cell propagation, recent evidence supports the notion that failure of intracellular protein clearance mechanisms (e.g. autophagy, unfolded protein response, proteolysis) might play a role in the process of -syn aggregation, release and subsequent accumulation of -syn pathological species in donor and acceptor cells.

• #12 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  A new field of investigation derives from the recent description of a prion-like spreading pathology of alpha-syn in MSA. […] Recent studies have pointed out the role of specific alpha-syn strains in the pathogenesis of synucleinopathies. […] Impaired protein degradation may also be involved in alpha-syn accumulation, as suggested by the description of a possible role of autophagic and proteasomal dysfunction in the disease. […] Mitochondria play an important role in several neurodegenerative diseases and, in particular, they have proven to be crucial in the pathogenesis of PD. […] Several groups have also investigated the role of mitochondria in MSA. […] After the recent description of mutations in COQ2 gene, encoding one of the enzymes involved in Coenzyme Q10 (CoQ10) biosynthesis, in familial and sporadic cases of MSA, the theme of a mitochondrial role in the pathogenesis of the disease has gained new and wider interest.

• #13 The neuropathology of multiple system atrophy and its therapeutic implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5954415/

  Given the high levels and widespread distribution of -syn aggregates in MSA, it is possible that both propagation and oligodendroglial -syn expression might be occurring simultaneously. […] Supporting the possibility of propagation, several studies have shown that -syn aggregates can transmit from neuron to neuron, neuron to astroglial and oligodendroglial cells, and oligodendroglial to astroglial cells, leading to neuronal dysfunction, apoptosis and neuroinflammation. […] Moreover, recent studies have shown that injection of homogenates from MSA brains propagate -syn pathology in a prion-like fashion in the murine brain. […] Whether its origin is intracellular or due to cell-to-cell propagation, recent evidence supports the notion that failure of intracellular protein clearance mechanisms (e.g. autophagy, unfolded protein response, proteolysis) might play a role in the process of -syn aggregation, release and subsequent accumulation of -syn pathological species in donor and acceptor cells.

• #14 Models of multiple system atrophy | Experimental & Molecular Medicine

  https://www.nature.com/articles/s12276-019-0346-8

  A study by Peng et al. showed differences between GCI–synuclein and LB–synuclein. These inclusions are conformationally and biologically distinct. GCI–synuclein is 1000-fold more potent than LB–synuclein in seeding the aggregation of monomeric -synuclein, which may explain the highly aggressive and rapidly progressive nature of MSA symptoms. […] The mechanisms of the accumulation of -synuclein in oligodendrocytes are still unknown. Several hypotheses have provided possible explanations as to how GCIs form. One possibility is that they form through the induced expression and aggregation of -synuclein in oligodendrocytes and other glial cells under disease conditions, but there is little evidence to support this cell-autonomous mechanism. An alternative explanation is that they form through the uptake of -synuclein secreted from neurons by oligodendrocytes.

• #15 Multiple System Atrophy-D Maybe Something Altogether–Different

  https://practicalneurology.com/diseases-diagnoses/movement-disorders/multiple-system-atrophy-d-maybe-something-altogetherdifferent/30257/

  The prion hypothesis, a theory that has been gaining support, was presented as the plenary lecture. Dr. Stanley Prusiner discussed experiments in which -synuclein samples from the brains of 14 patients who had MSA were transmitted to homozygous mice. After an incubation of 120 days, the mice developed neurodegeneration that was accompanied by deposition of -synuclein in cell bodies and axons. Control, sham-infected mice as well as those infected with -synuclein from the brains of patients who had PD did not develop neurodegeneration. Although controversial, these data are compelling and support the idea that despite clinical and pathologic similarities, MSA and PD are distinct points on a spectrum of neurodegeneration. […] As with most neurodegenerative diseases, we are at a fork in the road, with one path leading toward disease-modifying treatments and the other to symptomatic management. For the latter, currently in phase 2 trials, TD-9855 is being studied for the treatment of neurogenic orthostatic hypotension, as a daily-dose compound with vasogenic tone properties. For disease modification, studies of possible therapies run the gamut from autophagy, to active immunization, vaccination, and stem cells.

• #16 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  A new field of investigation derives from the recent description of a prion-like spreading pathology of alpha-syn in MSA. […] Recent studies have pointed out the role of specific alpha-syn strains in the pathogenesis of synucleinopathies. […] Impaired protein degradation may also be involved in alpha-syn accumulation, as suggested by the description of a possible role of autophagic and proteasomal dysfunction in the disease. […] Mitochondria play an important role in several neurodegenerative diseases and, in particular, they have proven to be crucial in the pathogenesis of PD. […] Several groups have also investigated the role of mitochondria in MSA. […] After the recent description of mutations in COQ2 gene, encoding one of the enzymes involved in Coenzyme Q10 (CoQ10) biosynthesis, in familial and sporadic cases of MSA, the theme of a mitochondrial role in the pathogenesis of the disease has gained new and wider interest.

• #17 The neuropathology of multiple system atrophy and its therapeutic implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5954415/

  Given the high levels and widespread distribution of -syn aggregates in MSA, it is possible that both propagation and oligodendroglial -syn expression might be occurring simultaneously. […] Supporting the possibility of propagation, several studies have shown that -syn aggregates can transmit from neuron to neuron, neuron to astroglial and oligodendroglial cells, and oligodendroglial to astroglial cells, leading to neuronal dysfunction, apoptosis and neuroinflammation. […] Moreover, recent studies have shown that injection of homogenates from MSA brains propagate -syn pathology in a prion-like fashion in the murine brain. […] Whether its origin is intracellular or due to cell-to-cell propagation, recent evidence supports the notion that failure of intracellular protein clearance mechanisms (e.g. autophagy, unfolded protein response, proteolysis) might play a role in the process of -syn aggregation, release and subsequent accumulation of -syn pathological species in donor and acceptor cells.

• #18 Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-020-0185-5

  Increasing numbers of investigations about autophagy dysregulation in MSA pathology have been published in recent years. Indeed, in vitro observations have revealed that pharmacologic and genetic inhibition of autophagy causes significant accumulation of both endogenous and exogenously applied -syn in oligodendroglial cells. Dysfunction of the autophagy-lysosome system in MSA is also regulated by transcriptional and epigenetic mechanisms. […] Iron accumulation in affected areas of MSA brains is a pathological hallmark of the disease. In addition to the increase in the total iron concentration, expression of the iron storage protein, ferritin, is increased, and the iron export protein, ferroportin, is decreased in the pons of patients with MSA, suggesting the presence of dysregulated bioavailability of iron in MSA brains.

• #19 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  A new field of investigation derives from the recent description of a prion-like spreading pathology of alpha-syn in MSA. […] Recent studies have pointed out the role of specific alpha-syn strains in the pathogenesis of synucleinopathies. […] Impaired protein degradation may also be involved in alpha-syn accumulation, as suggested by the description of a possible role of autophagic and proteasomal dysfunction in the disease. […] Mitochondria play an important role in several neurodegenerative diseases and, in particular, they have proven to be crucial in the pathogenesis of PD. […] Several groups have also investigated the role of mitochondria in MSA. […] After the recent description of mutations in COQ2 gene, encoding one of the enzymes involved in Coenzyme Q10 (CoQ10) biosynthesis, in familial and sporadic cases of MSA, the theme of a mitochondrial role in the pathogenesis of the disease has gained new and wider interest.

• #20 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  A new field of investigation derives from the recent description of a prion-like spreading pathology of alpha-syn in MSA. […] Recent studies have pointed out the role of specific alpha-syn strains in the pathogenesis of synucleinopathies. […] Impaired protein degradation may also be involved in alpha-syn accumulation, as suggested by the description of a possible role of autophagic and proteasomal dysfunction in the disease. […] Mitochondria play an important role in several neurodegenerative diseases and, in particular, they have proven to be crucial in the pathogenesis of PD. […] Several groups have also investigated the role of mitochondria in MSA. […] After the recent description of mutations in COQ2 gene, encoding one of the enzymes involved in Coenzyme Q10 (CoQ10) biosynthesis, in familial and sporadic cases of MSA, the theme of a mitochondrial role in the pathogenesis of the disease has gained new and wider interest.

• #21 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives – PubMed

  https://pubmed.ncbi.nlm.nih.gov/31300049/

  Afterwards, several recent achievements in MSA research involving mitochondrial biology are described, including the role of COQ2 mutations, Coenzyme Q10 reduction, respiratory chain dysfunction and altered mitochondrial mass. […] Some hints are provided about alternative pathogenic mechanisms, including inflammation and impaired autophagy. […] Overall, the present review provides a comprehensive and up-to-date overview of the mechanisms underlying MSA pathogenesis.

• #22 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives – PubMed

  https://pubmed.ncbi.nlm.nih.gov/31300049/

  Afterwards, several recent achievements in MSA research involving mitochondrial biology are described, including the role of COQ2 mutations, Coenzyme Q10 reduction, respiratory chain dysfunction and altered mitochondrial mass. […] Some hints are provided about alternative pathogenic mechanisms, including inflammation and impaired autophagy. […] Overall, the present review provides a comprehensive and up-to-date overview of the mechanisms underlying MSA pathogenesis.

• #23 Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature

  https://www.mdpi.com/1422-0067/24/6/5281

  Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are uncommon multifactorial atypical Parkinsonian syndromes, expressed by various clinical features. […] The purpose of this study was to critically review the genetics of MSA and PSP and their involvement in the pathogenesis. […] Although familial MSA cases have been reported, the hereditary nature could not be demonstrated. […] COQ2 mutations were involved in familial and sporadic MSA, without being reproduced in various clinical populations. […] In terms of the genetics of the cohort, synuclein alpha (SNCA) polymorphisms were correlated with an elevated likelihood of manifesting MSA in Caucasians, but a causal effect relationship could not be demonstrated. […] Despite the limited evidence, it seems that genetics influence the susceptibility to MSA and PSP.

• #24 Genetics of Multiple System Atrophy and Progressive Supranuclear Palsy: A Systemized Review of the Literature

  https://www.mdpi.com/1422-0067/24/6/5281

  Multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) are uncommon multifactorial atypical Parkinsonian syndromes, expressed by various clinical features. […] The purpose of this study was to critically review the genetics of MSA and PSP and their involvement in the pathogenesis. […] Although familial MSA cases have been reported, the hereditary nature could not be demonstrated. […] COQ2 mutations were involved in familial and sporadic MSA, without being reproduced in various clinical populations. […] In terms of the genetics of the cohort, synuclein alpha (SNCA) polymorphisms were correlated with an elevated likelihood of manifesting MSA in Caucasians, but a causal effect relationship could not be demonstrated. […] Despite the limited evidence, it seems that genetics influence the susceptibility to MSA and PSP.

• #25 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives – PubMed

  https://pubmed.ncbi.nlm.nih.gov/31300049/

  Afterwards, several recent achievements in MSA research involving mitochondrial biology are described, including the role of COQ2 mutations, Coenzyme Q10 reduction, respiratory chain dysfunction and altered mitochondrial mass. […] Some hints are provided about alternative pathogenic mechanisms, including inflammation and impaired autophagy. […] Overall, the present review provides a comprehensive and up-to-date overview of the mechanisms underlying MSA pathogenesis.

• #26 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  All these studies, observed from a comprehensive point of view, point towards a crucial role of mitochondria in the pathogenesis of MSA. […] Although the present review is specifically focused on alpha-syn accumulation and mitochondrial dysfunction, it must be acknowledged that other hypotheses have been proposed to explain the pathogenesis of MSA. […] The role of impaired protein degradation has to also be considered when discussing the pathogenic mechanisms of MSA. […] The finding of an increased iron level in specific brain regions of MSA patients has led to the hypothesis that iron metabolism dysregulation may play a role in the pathogenesis of the disease. […] The peculiar neuropathological pattern of the disease, characterized by alpha-syn accumulation in oligodendrocytes, has led many investigators to focus on this particular aspect and to hypothesize that MSA primarily represents an oligodendrogliopathy, with a secondary neuronal involvement.

• #27

  https://link.springer.com/article/10.1007/s00702-021-02383-3

  The exact mechanisms underlying the formation of distinct strains are not clarified, but glial-specific features of the intracellular milieu are thought to promote the selective -synuclein misfolding and accumulation within glial cells and partially justify the different behavior of -synuclein in MSA compared to other -synucleinopathies. […] Other pathophysiological mechanisms potentially contributing to neurodegeneration have been described including mitochondrial dysfunction, alteration in cell-death regulatory mechanisms and oxidative stress. […] By inducing microglial activation, -synuclein may contribute to neuroinflammation, thus exacerbating and accelerating the neurodegeneration.

• #28 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  All these studies, observed from a comprehensive point of view, point towards a crucial role of mitochondria in the pathogenesis of MSA. […] Although the present review is specifically focused on alpha-syn accumulation and mitochondrial dysfunction, it must be acknowledged that other hypotheses have been proposed to explain the pathogenesis of MSA. […] The role of impaired protein degradation has to also be considered when discussing the pathogenic mechanisms of MSA. […] The finding of an increased iron level in specific brain regions of MSA patients has led to the hypothesis that iron metabolism dysregulation may play a role in the pathogenesis of the disease. […] The peculiar neuropathological pattern of the disease, characterized by alpha-syn accumulation in oligodendrocytes, has led many investigators to focus on this particular aspect and to hypothesize that MSA primarily represents an oligodendrogliopathy, with a secondary neuronal involvement.

• #29

  https://link.springer.com/article/10.1007/s00702-021-02383-3

  Multiple System Atrophy (MSA) is a rare, fatal neurodegenerative disorder. Its etiology and exact pathogenesis still remain poorly understood and currently no disease-modifying therapy is available to halt or slow down this detrimental neurodegenerative process. Hallmarks of the disease are -synuclein rich glial cytoplasmic inclusions (GCIs). Neuropathologically, various degrees of striatonigral degeneration (SND) and olivopontocerebellar atrophy (OPCA) can be observed. […] The etiology and pathogenesis of MSA still remains largely elusive; nonetheless since the original description of the GCIs in SND, OPCA and Shy Drager syndrome in 1989, several steps forward have been made to untangle some key pathogenic events in MSA. […] Although the clinical presentation of MSA seems to be the expression of an underlying diffuse neuronal cell loss, the strict correlation between disease severity and GCIs load, along with evidence coming from in vitro and in vivo animal models, supports the notion that MSA is a primary oligodendrogliopathy with secondary neurodegeneration.

• #30 Recent advances in multiple system atrophy | JNEUROLOGY

  https://www.jneurology.com/articles/recent-advances-in-multiple-system-atrophy-neuromed-1-1002.php

  The earliest stages of MSA pathogenesis are likely to involve a relocation of p25 (TPPP – tubulin polymerization-promoting protein), an oligodendroglia-specific phosphoprotein and stabilizer of microtubules and myelin integrity, from the myelin sheaths to the oligodendroglial soma. This is associated with myelin dysfunction, reduction of full-length MBP, demyelination of small-caliber axons and an increase in oligodendroglial soma size, preceding Syn aggregation. The interaction between p25 and Syn promotes phosphorylation and aggregation into insoluble oligomers and GCIs implies that mitochondrial dysfunction can lead to secondary p25 relocation, probably linked to dysregulation of lipid metabolism and dysfunctional myelination, probably a fundamental event in MSA pathogenesis. […] Evidence from animal models and human postmortem studies suggest that the accumulation of misfolded Syn plays a central role in the disease process, which can be considered a synucleinopathy with specific glioneuronal degeneration, associated with early myelin dysfunction and neuronal degeneration related to retrograde axonal disease. Although one may speculate that primary neuronal pathology leads to secondary oligodendroglia degeneration as suggested by the finding that NCIs exist in areas lacking GCIs, the fact that distribution and severity of neurodegeneration reflect sub-regional GCI densities supports the hypothesis of a primary oligodendrogliopathy.

• #31 Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-020-0185-5

  Glial cytoplasmic inclusions (GCIs), the diagnostic hallmark of MSA, are fibrillary structures composed of misfolded -synuclein. This important discovery of -syn-immunoreactive inclusions in oligodendrocytes (OLGs) raised fundamental questions: 1) what is the primary event which triggers the generation of misfolded -syn leading to the formation of GCIs? 2) how does -syn accumulate in OLGs, which produce few -syn mRNA transcripts? and 3) how much are other glial cells involved in the pathogenesis of GCIs and neurodegeneration? […] The detection of widespread myelin degeneration as the initial event in MSA brains has led to the concept of primary oligodendrogliopathy, suggesting that the pathogenesis of MSA is regulated primarily by oligodendroglial dysfunction. Supporting evidence shows that about 50% of non–syn-expressing OLGs in pontine fiber tracts of MSA brains have abnormal accumulation of TPPP/p25 and are enlarged in cell size. TPPP/p25 is an oligodendroglial-specific phosphoprotein and colocalizes with myelin basic protein (MBP) in normal human brains, and this colocalization is lost in MSA.

• #32 Recent advances in multiple system atrophy | JNEUROLOGY

  https://www.jneurology.com/articles/recent-advances-in-multiple-system-atrophy-neuromed-1-1002.php

  The earliest stages of MSA pathogenesis are likely to involve a relocation of p25 (TPPP – tubulin polymerization-promoting protein), an oligodendroglia-specific phosphoprotein and stabilizer of microtubules and myelin integrity, from the myelin sheaths to the oligodendroglial soma. This is associated with myelin dysfunction, reduction of full-length MBP, demyelination of small-caliber axons and an increase in oligodendroglial soma size, preceding Syn aggregation. The interaction between p25 and Syn promotes phosphorylation and aggregation into insoluble oligomers and GCIs implies that mitochondrial dysfunction can lead to secondary p25 relocation, probably linked to dysregulation of lipid metabolism and dysfunctional myelination, probably a fundamental event in MSA pathogenesis. […] Evidence from animal models and human postmortem studies suggest that the accumulation of misfolded Syn plays a central role in the disease process, which can be considered a synucleinopathy with specific glioneuronal degeneration, associated with early myelin dysfunction and neuronal degeneration related to retrograde axonal disease. Although one may speculate that primary neuronal pathology leads to secondary oligodendroglia degeneration as suggested by the finding that NCIs exist in areas lacking GCIs, the fact that distribution and severity of neurodegeneration reflect sub-regional GCI densities supports the hypothesis of a primary oligodendrogliopathy.

• #33 Recent advances in multiple system atrophy | JNEUROLOGY

  https://www.jneurology.com/articles/recent-advances-in-multiple-system-atrophy-neuromed-1-1002.php

  The earliest stages of MSA pathogenesis are likely to involve a relocation of p25 (TPPP – tubulin polymerization-promoting protein), an oligodendroglia-specific phosphoprotein and stabilizer of microtubules and myelin integrity, from the myelin sheaths to the oligodendroglial soma. This is associated with myelin dysfunction, reduction of full-length MBP, demyelination of small-caliber axons and an increase in oligodendroglial soma size, preceding Syn aggregation. The interaction between p25 and Syn promotes phosphorylation and aggregation into insoluble oligomers and GCIs implies that mitochondrial dysfunction can lead to secondary p25 relocation, probably linked to dysregulation of lipid metabolism and dysfunctional myelination, probably a fundamental event in MSA pathogenesis. […] Evidence from animal models and human postmortem studies suggest that the accumulation of misfolded Syn plays a central role in the disease process, which can be considered a synucleinopathy with specific glioneuronal degeneration, associated with early myelin dysfunction and neuronal degeneration related to retrograde axonal disease. Although one may speculate that primary neuronal pathology leads to secondary oligodendroglia degeneration as suggested by the finding that NCIs exist in areas lacking GCIs, the fact that distribution and severity of neurodegeneration reflect sub-regional GCI densities supports the hypothesis of a primary oligodendrogliopathy.

• #34 Exploring Myelin Dysfunction in Multiple System Atrophy

  https://www.en-journal.org/journal/view.html?uid=244

  Thus, reductions in the amount of these proteins in myelin could account for myelin dysfunction observed in MSA brains. […] It is possible the dysregulation of lipid homeostasis could contribute to myelin dysfunction in the early stages of MSA. […] Overall, these lines of evidence suggest ABCA8 is upregulated during the earlier stages of MSA, and may contribute to aberrant -synuclein production and aggregation through dysregulated lipid homeostasis.

• #35 The neuropathology of multiple system atrophy and its therapeutic implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5954415/

  The principal consequences of -syn-induced oligodendroglial degeneration are the loss of trophic support to neurons and demyelination, which in turn lead to further neurodegeneration. […] This secondary neurodegeneration may explain the lack of response to L-DOPA observed in MSA patients and the fast progression of this devastating disease. […] One of the most relevant characteristics of MSA is the selective neuronal loss and axonal degeneration in the central autonomic, striatonigral and olivopontocerebellar networks, with cell loss also present in autonomic brain stem nuclei. […] In this sense, it is likely that approaches that lead to a reduction in -syn accumulation in both oligodendrocytes and neurons may be more effective that cell-specific approaches. […] Moreover, the important component of -syn propagation and the pathological accumulation of -syn within two different cell types, and its orphan disease status make MSA a strong synucleinopathy candidate for accelerated drug discovery.

• #36 The neuropathology of multiple system atrophy and its therapeutic implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5954415/

  The principal consequences of -syn-induced oligodendroglial degeneration are the loss of trophic support to neurons and demyelination, which in turn lead to further neurodegeneration. […] This secondary neurodegeneration may explain the lack of response to L-DOPA observed in MSA patients and the fast progression of this devastating disease. […] One of the most relevant characteristics of MSA is the selective neuronal loss and axonal degeneration in the central autonomic, striatonigral and olivopontocerebellar networks, with cell loss also present in autonomic brain stem nuclei. […] In this sense, it is likely that approaches that lead to a reduction in -syn accumulation in both oligodendrocytes and neurons may be more effective that cell-specific approaches. […] Moreover, the important component of -syn propagation and the pathological accumulation of -syn within two different cell types, and its orphan disease status make MSA a strong synucleinopathy candidate for accelerated drug discovery.

• #37 Recent advances in multiple system atrophy | JNEUROLOGY

  https://www.jneurology.com/articles/recent-advances-in-multiple-system-atrophy-neuromed-1-1002.php

  The earliest stages of MSA pathogenesis are likely to involve a relocation of p25 (TPPP – tubulin polymerization-promoting protein), an oligodendroglia-specific phosphoprotein and stabilizer of microtubules and myelin integrity, from the myelin sheaths to the oligodendroglial soma. This is associated with myelin dysfunction, reduction of full-length MBP, demyelination of small-caliber axons and an increase in oligodendroglial soma size, preceding Syn aggregation. The interaction between p25 and Syn promotes phosphorylation and aggregation into insoluble oligomers and GCIs implies that mitochondrial dysfunction can lead to secondary p25 relocation, probably linked to dysregulation of lipid metabolism and dysfunctional myelination, probably a fundamental event in MSA pathogenesis. […] Evidence from animal models and human postmortem studies suggest that the accumulation of misfolded Syn plays a central role in the disease process, which can be considered a synucleinopathy with specific glioneuronal degeneration, associated with early myelin dysfunction and neuronal degeneration related to retrograde axonal disease. Although one may speculate that primary neuronal pathology leads to secondary oligodendroglia degeneration as suggested by the finding that NCIs exist in areas lacking GCIs, the fact that distribution and severity of neurodegeneration reflect sub-regional GCI densities supports the hypothesis of a primary oligodendrogliopathy.

• #38 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  All these studies, observed from a comprehensive point of view, point towards a crucial role of mitochondria in the pathogenesis of MSA. […] Although the present review is specifically focused on alpha-syn accumulation and mitochondrial dysfunction, it must be acknowledged that other hypotheses have been proposed to explain the pathogenesis of MSA. […] The role of impaired protein degradation has to also be considered when discussing the pathogenic mechanisms of MSA. […] The finding of an increased iron level in specific brain regions of MSA patients has led to the hypothesis that iron metabolism dysregulation may play a role in the pathogenesis of the disease. […] The peculiar neuropathological pattern of the disease, characterized by alpha-syn accumulation in oligodendrocytes, has led many investigators to focus on this particular aspect and to hypothesize that MSA primarily represents an oligodendrogliopathy, with a secondary neuronal involvement.

• #39 Models of multiple system atrophy | Experimental & Molecular Medicine

  https://www.nature.com/articles/s12276-019-0346-8

  A failure to discard proteins through cellular degradation pathways may lead to the production of toxic aggregates that may incorporate into GCIs and cause oligodendrocyte dysfunction. […] The activation of astrocytes and microglia has been observed in the brains of MSA patients, as well as in those of transgenic models of MSA. […] The injection of GCI extract into the mouse brain causes localized microgliosis, as well as astrogliosis. […] In vitro and in vivo models have been developed to obtain a better understanding of MSA pathophysiology. […] MSA pathophysiology has been addressed at the cellular level through modified gene expression. […] The transgenic expression of the -synuclein gene under oligodendrocyte-specific promoters has been used to create mouse models of MSA. […] The accumulation of -synuclein in oligodendroglia has been found in all three oligodendrocyte-specific promoter-driven human -synuclein tg mice. However, each of these mice displayed distinct patterns of pathological changes that do not precisely replicate human MSA pathology. […] Recent studies have suggested that GCIs are generated through the transfer of -synuclein from neurons to oligodendrocytes.

• #40 Models of multiple system atrophy | Experimental & Molecular Medicine

  https://www.nature.com/articles/s12276-019-0346-8

  A failure to discard proteins through cellular degradation pathways may lead to the production of toxic aggregates that may incorporate into GCIs and cause oligodendrocyte dysfunction. […] The activation of astrocytes and microglia has been observed in the brains of MSA patients, as well as in those of transgenic models of MSA. […] The injection of GCI extract into the mouse brain causes localized microgliosis, as well as astrogliosis. […] In vitro and in vivo models have been developed to obtain a better understanding of MSA pathophysiology. […] MSA pathophysiology has been addressed at the cellular level through modified gene expression. […] The transgenic expression of the -synuclein gene under oligodendrocyte-specific promoters has been used to create mouse models of MSA. […] The accumulation of -synuclein in oligodendroglia has been found in all three oligodendrocyte-specific promoter-driven human -synuclein tg mice. However, each of these mice displayed distinct patterns of pathological changes that do not precisely replicate human MSA pathology. […] Recent studies have suggested that GCIs are generated through the transfer of -synuclein from neurons to oligodendrocytes.

• #41 Multiple System Atrophy: Advances in Diagnosis and Therapy

  https://www.e-jmd.org/journal/view.php?number=416

  The role of inflammatory pathogenesis has also offered important insights, with significant increases in HLA-DR+ microglia in the putamen and substantia nigra of patients with MSA compared with controls and significant increases in CD3+, CD4+, and CD8+ T cells in these brain regions. […] Neuroinflammation and oligodendroglia changes contribute to MSA pathogenesis.

• #42

  https://link.springer.com/article/10.1007/s00415-024-12269-5

  Targeting the misfolding and aggregation of -synuclein has always been one of the major treatment strategies for MSA. […] The impairment of protein processing and degradation has been implicated in the pathogenesis of -synuclein aggregation based on some preclinical evidence. […] There was growing evidence that brain inflammation played a crucial role in the pathogenesis of MSA. […] The goal of neuroprotection treatment is to provide the brain with the necessary factors to support the neurons and to prevent neurodegenerative changes at the molecular level. […] MSA is driven by combined defects like many other NDDs. […] Therefore, designing combinatorial and personalized therapeutic strategies to effectively halt the MSA will be a promising and compelling perspective in future based on the better understanding the molecular mechanisms and development of biomarkers.

• #43 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  All these studies, observed from a comprehensive point of view, point towards a crucial role of mitochondria in the pathogenesis of MSA. […] Although the present review is specifically focused on alpha-syn accumulation and mitochondrial dysfunction, it must be acknowledged that other hypotheses have been proposed to explain the pathogenesis of MSA. […] The role of impaired protein degradation has to also be considered when discussing the pathogenic mechanisms of MSA. […] The finding of an increased iron level in specific brain regions of MSA patients has led to the hypothesis that iron metabolism dysregulation may play a role in the pathogenesis of the disease. […] The peculiar neuropathological pattern of the disease, characterized by alpha-syn accumulation in oligodendrocytes, has led many investigators to focus on this particular aspect and to hypothesize that MSA primarily represents an oligodendrogliopathy, with a secondary neuronal involvement.

• #44 Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-020-0185-5

  Increasing numbers of investigations about autophagy dysregulation in MSA pathology have been published in recent years. Indeed, in vitro observations have revealed that pharmacologic and genetic inhibition of autophagy causes significant accumulation of both endogenous and exogenously applied -syn in oligodendroglial cells. Dysfunction of the autophagy-lysosome system in MSA is also regulated by transcriptional and epigenetic mechanisms. […] Iron accumulation in affected areas of MSA brains is a pathological hallmark of the disease. In addition to the increase in the total iron concentration, expression of the iron storage protein, ferritin, is increased, and the iron export protein, ferroportin, is decreased in the pons of patients with MSA, suggesting the presence of dysregulated bioavailability of iron in MSA brains.

• #45 Alterity Therapeutics Granted U.S. FDA Fast Track Designation for ATH434 to Treat Multiple System Atrophy | MarketScreener

  https://www.marketscreener.com/quote/stock/ALTERITY-THERAPEUTICS-LIM-57291688/news/Alterity-Therapeutics-Granted-U-S-FDA-Fast-Track-Designation-for-ATH434-to-Treat-Multiple-System-At-49825276/

  ATH434 has been shown preclinically to reduce -synuclein pathology and preserve neuronal function by restoring normal iron balance in the brain in preclinical models. […] As an iron chaperone, it has excellent potential to treat Parkinsons disease as well as various Parkinsonian disorders such as Multiple System Atrophy (MSA). […] Both dose levels stabilized or reduced iron accumulation in MSA affected brain regions with trends in preservation of brain volume. […] A pathological hallmark of MSA is the accumulation of the protein -synuclein within glia, the support cells of the central nervous system, and neuron loss in multiple brain regions.

• #46 Iron Chaperone Granted Fast Track Status for Multiple System Atrophy

  https://www.empr.com/news/iron-chaperone-granted-fast-track-status-for-multiple-system-atrophy/

  MSA is a progressive neurodegenerative disorder characterized by slowed movement and/or rigidity, autonomic instability, and impaired balance and/or coordination. […] Administered orally, ATH434 is designed to reduce -synuclein aggregation and oxidative stress by binding to and redistributing excess loosely bound iron in the brain. This approach is expected to limit neurodegeneration in patients with MSA. […] This designation reinforces the potential of ATH434 as demonstrated by recent scientific findings related to its mechanism of action and the robust and clinically meaningful efficacy from our double-blind phase 2 clinical trial.

• #47 Insights into the pathogenesis of multiple system atrophy: focus on glial cytoplasmic inclusions | Translational Neurodegeneration | Full Text

  https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-020-0185-5

  Increasing numbers of investigations about autophagy dysregulation in MSA pathology have been published in recent years. Indeed, in vitro observations have revealed that pharmacologic and genetic inhibition of autophagy causes significant accumulation of both endogenous and exogenously applied -syn in oligodendroglial cells. Dysfunction of the autophagy-lysosome system in MSA is also regulated by transcriptional and epigenetic mechanisms. […] Iron accumulation in affected areas of MSA brains is a pathological hallmark of the disease. In addition to the increase in the total iron concentration, expression of the iron storage protein, ferritin, is increased, and the iron export protein, ferroportin, is decreased in the pons of patients with MSA, suggesting the presence of dysregulated bioavailability of iron in MSA brains.

• #48 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives – PubMed

  https://pubmed.ncbi.nlm.nih.gov/31300049/

  Afterwards, several recent achievements in MSA research involving mitochondrial biology are described, including the role of COQ2 mutations, Coenzyme Q10 reduction, respiratory chain dysfunction and altered mitochondrial mass. […] Some hints are provided about alternative pathogenic mechanisms, including inflammation and impaired autophagy. […] Overall, the present review provides a comprehensive and up-to-date overview of the mechanisms underlying MSA pathogenesis.

• #49 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  The temporal sequence of pathogenic events is still obscure and it is not clear which of the proposed causative mechanisms (e.g. protein accumulation, mitochondrial dysfunction, inflammation) represents the primary episode which triggers the whole pathogenic cascade. […] Therefore, it is intriguing to hypothesize that MSA represents a multifactorial disease caused by the combined effect of multiple hits.

• #50 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives | Acta Neuropathologica Communications | Full Text

  https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0730-6

  The temporal sequence of pathogenic events is still obscure and it is not clear which of the proposed causative mechanisms (e.g. protein accumulation, mitochondrial dysfunction, inflammation) represents the primary episode which triggers the whole pathogenic cascade. […] Therefore, it is intriguing to hypothesize that MSA represents a multifactorial disease caused by the combined effect of multiple hits.

• #51

  https://link.springer.com/article/10.1007/s00415-024-12269-5

  Targeting the misfolding and aggregation of -synuclein has always been one of the major treatment strategies for MSA. […] The impairment of protein processing and degradation has been implicated in the pathogenesis of -synuclein aggregation based on some preclinical evidence. […] There was growing evidence that brain inflammation played a crucial role in the pathogenesis of MSA. […] The goal of neuroprotection treatment is to provide the brain with the necessary factors to support the neurons and to prevent neurodegenerative changes at the molecular level. […] MSA is driven by combined defects like many other NDDs. […] Therefore, designing combinatorial and personalized therapeutic strategies to effectively halt the MSA will be a promising and compelling perspective in future based on the better understanding the molecular mechanisms and development of biomarkers.

• #52 Exploring Myelin Dysfunction in Multiple System Atrophy

  https://www.en-journal.org/journal/view.html?uid=244

  Multiple system atrophy (MSA) is a rare, yet fatal neurodegenerative disease that presents clinically with autonomic failure in combination with parkinsonism or cerebellar ataxia. […] The definitive pathology of MSA is the presence of -synuclein aggregates in the brain and therefore MSA is classified as an -synucleinopathy, together with Parkinson’s disease and dementia with Lewy bodies. […] The sequence of pathological events of MSA is now recognized as abnormal protein redistributions in oligodendrocytes first, followed by myelin dysfunction and then neurodegeneration. […] Current understanding of MSA neuropathology is that both grey and white matter pathology occur in the form of neurodegeneration, gliosis, myelin loss and axonal degeneration. […] The most consistent pathological hallmark of MSA is glial cytoplasmic inclusions (GCIs).

• #53

  https://link.springer.com/article/10.1007/s00415-024-12269-5

  However, there are still a few key unanswered questions in the MSA pathogenic cascade, such as the timing of GCIs formation, the clear mechanism of interplay between neuron and glia, etc. […] The most straightforward therapeutic target and treatment strategy is directed against pathological oligomer -synuclein. […] Treatment strategies targeting -synuclein have been widely adopted and evaluated in clinical trials. […] The development outlined above suggests that ASO is likely to become a significant new therapeutic category for neurodegenerative diseases and rare diseases. […] Given that intracellular aggregation of -synuclein plays a critical role in the MSA pathology, reducing the -synuclein protein production using ASO targeting SNCA gene is a straightforward and promising mechanism of action, although current research in this area remains at an early stage.

• #54

  https://link.springer.com/article/10.1007/s00415-024-12269-5

  However, there are still a few key unanswered questions in the MSA pathogenic cascade, such as the timing of GCIs formation, the clear mechanism of interplay between neuron and glia, etc. […] The most straightforward therapeutic target and treatment strategy is directed against pathological oligomer -synuclein. […] Treatment strategies targeting -synuclein have been widely adopted and evaluated in clinical trials. […] The development outlined above suggests that ASO is likely to become a significant new therapeutic category for neurodegenerative diseases and rare diseases. […] Given that intracellular aggregation of -synuclein plays a critical role in the MSA pathology, reducing the -synuclein protein production using ASO targeting SNCA gene is a straightforward and promising mechanism of action, although current research in this area remains at an early stage.

• #55

  https://link.springer.com/article/10.1007/s00415-024-12269-5

  However, there are still a few key unanswered questions in the MSA pathogenic cascade, such as the timing of GCIs formation, the clear mechanism of interplay between neuron and glia, etc. […] The most straightforward therapeutic target and treatment strategy is directed against pathological oligomer -synuclein. […] Treatment strategies targeting -synuclein have been widely adopted and evaluated in clinical trials. […] The development outlined above suggests that ASO is likely to become a significant new therapeutic category for neurodegenerative diseases and rare diseases. […] Given that intracellular aggregation of -synuclein plays a critical role in the MSA pathology, reducing the -synuclein protein production using ASO targeting SNCA gene is a straightforward and promising mechanism of action, although current research in this area remains at an early stage.

• #56

  https://link.springer.com/article/10.1007/s00415-024-12269-5

  However, there are still a few key unanswered questions in the MSA pathogenic cascade, such as the timing of GCIs formation, the clear mechanism of interplay between neuron and glia, etc. […] The most straightforward therapeutic target and treatment strategy is directed against pathological oligomer -synuclein. […] Treatment strategies targeting -synuclein have been widely adopted and evaluated in clinical trials. […] The development outlined above suggests that ASO is likely to become a significant new therapeutic category for neurodegenerative diseases and rare diseases. […] Given that intracellular aggregation of -synuclein plays a critical role in the MSA pathology, reducing the -synuclein protein production using ASO targeting SNCA gene is a straightforward and promising mechanism of action, although current research in this area remains at an early stage.

• #57

  https://link.springer.com/article/10.1007/s00415-024-12269-5

  Targeting the misfolding and aggregation of -synuclein has always been one of the major treatment strategies for MSA. […] The impairment of protein processing and degradation has been implicated in the pathogenesis of -synuclein aggregation based on some preclinical evidence. […] There was growing evidence that brain inflammation played a crucial role in the pathogenesis of MSA. […] The goal of neuroprotection treatment is to provide the brain with the necessary factors to support the neurons and to prevent neurodegenerative changes at the molecular level. […] MSA is driven by combined defects like many other NDDs. […] Therefore, designing combinatorial and personalized therapeutic strategies to effectively halt the MSA will be a promising and compelling perspective in future based on the better understanding the molecular mechanisms and development of biomarkers.

• #58 Exidavnemab phase 2a study expanded to include MSA patients | BI

  https://www.gurufocus.com/news/2843140/exidavnemab-phase-2a-study-expanded-to-include-msa-patients-bioa-stock-news

  BioArctic AB (BIOA) has announced the expansion of its EXIST Phase 2a clinical trial to incorporate patients suffering from Multiple System Atrophy (MSA). […] Exidavnemab, a monoclonal antibody developed by BioArctic, selectively targets alpha-synuclein aggregates, which are believed to contribute to the pathogenesis of neuronal synuclein diseases such as MSA and Parkinsons. […] Multiple System Atrophy is a rapidly progressing and fatal neurodegenerative disorder that affects the central and autonomic nervous systems. The disease is characterized by the aggregation of the protein alpha-synuclein, leading to severe symptoms affecting basic bodily functions, including balance, movement, and autonomic regulation. Currently, no treatments exist to cure or decelerate the progression of MSA. […] BioArctic’s trial expansion reflects a strategic move to address an unmet medical need by leveraging the common pathological pathway shared by MSA and Parkinson’s Disease. This could potentially position exidavnemab as a pioneering therapy within this challenging therapeutic area.

• #59 Understanding the pathogenesis of multiple system atrophy: state of the art and future perspectives – PubMed

  https://pubmed.ncbi.nlm.nih.gov/31300049/

  Afterwards, several recent achievements in MSA research involving mitochondrial biology are described, including the role of COQ2 mutations, Coenzyme Q10 reduction, respiratory chain dysfunction and altered mitochondrial mass. […] Some hints are provided about alternative pathogenic mechanisms, including inflammation and impaired autophagy. […] Overall, the present review provides a comprehensive and up-to-date overview of the mechanisms underlying MSA pathogenesis.

• #60 Alterity Therapeutics Granted U.S. FDA Fast Track Designation for ATH434 to Treat Multiple System Atrophy | MarketScreener

  https://www.marketscreener.com/quote/stock/ALTERITY-THERAPEUTICS-LIM-57291688/news/Alterity-Therapeutics-Granted-U-S-FDA-Fast-Track-Designation-for-ATH434-to-Treat-Multiple-System-At-49825276/

  ATH434 has been shown preclinically to reduce -synuclein pathology and preserve neuronal function by restoring normal iron balance in the brain in preclinical models. […] As an iron chaperone, it has excellent potential to treat Parkinsons disease as well as various Parkinsonian disorders such as Multiple System Atrophy (MSA). […] Both dose levels stabilized or reduced iron accumulation in MSA affected brain regions with trends in preservation of brain volume. […] A pathological hallmark of MSA is the accumulation of the protein -synuclein within glia, the support cells of the central nervous system, and neuron loss in multiple brain regions.

• #61 Alterity Therapeutics Announces Multiple Oral and Poster Presentations to be Featured at the International MSA Congress | ATHE Stock News

  https://www.stocktitan.net/news/ATHE/alterity-therapeutics-announces-multiple-oral-and-poster-xb235123ljbs.html

  ATH434 has been shown preclinically to reduce -synuclein pathology and preserve neuronal function by restoring normal iron balance in the brain in preclinical models. […] Positive results from the randomized, double-blind, placebo-controlled Phase 2 clinical trial in patients with MSA demonstrated robust clinical efficacy, target engagement on key biomarkers, and a favorable safety profile. […] MSA is a Parkinsonian disorder characterized by a variable combination of slowed movement and/or rigidity, autonomic instability that affects involuntary functions such as blood pressure maintenance and bladder control, and impaired balance and/or coordination that predisposes to falls. […] A pathological hallmark of MSA is the accumulation of the protein -synuclein within glia, the support cells of the central nervous system, and neuron loss in multiple brain regions.

• #62

  https://link.springer.com/article/10.1007/s00415-024-12269-5

  Targeting the misfolding and aggregation of -synuclein has always been one of the major treatment strategies for MSA. […] The impairment of protein processing and degradation has been implicated in the pathogenesis of -synuclein aggregation based on some preclinical evidence. […] There was growing evidence that brain inflammation played a crucial role in the pathogenesis of MSA. […] The goal of neuroprotection treatment is to provide the brain with the necessary factors to support the neurons and to prevent neurodegenerative changes at the molecular level. […] MSA is driven by combined defects like many other NDDs. […] Therefore, designing combinatorial and personalized therapeutic strategies to effectively halt the MSA will be a promising and compelling perspective in future based on the better understanding the molecular mechanisms and development of biomarkers.

• #63 ClinMed International Library

  https://clinmedjournals.org/articles/ijnn/ijnn-2-022.php?jid=ijnn

  Further research on the basic pathogenic mechanisms, the interplay of the disease process with various pathobiological and molecular changes, and the nature of possible genetic and environmental triggers that unmask its pathogenesis will be needed to develop optimal animal models, and to clarify the relations between the development of pathomorphology and clinical manifestations as a basis for early diagnosis and a disease-modifying treatment of this hitherto incurable devastating disorder.

• #64 The neuropathology of multiple system atrophy and its therapeutic implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5954415/

  The involvement of neuronal -syn accumulation as a main pathological event in MSA remains to be investigated. […] Nevertheless, according to the propagation model of MSA pathology, a reduction in the neuronal expression, release and accumulation of -syn may translate in a decrease in oligodendroglial -syn levels and lead to disease modification. […] It can be concluded that more research is needed to elucidate how neurons, oligodendrocytes and other glial types interplay at the origin of the MSA pathology and during the progression of the disease.

• #65 The neuropathology of multiple system atrophy and its therapeutic implications

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5954415/

  The involvement of neuronal -syn accumulation as a main pathological event in MSA remains to be investigated. […] Nevertheless, according to the propagation model of MSA pathology, a reduction in the neuronal expression, release and accumulation of -syn may translate in a decrease in oligodendroglial -syn levels and lead to disease modification. […] It can be concluded that more research is needed to elucidate how neurons, oligodendrocytes and other glial types interplay at the origin of the MSA pathology and during the progression of the disease.

• #66 Department of Therapeutics for Multiple System Atrophy | Graduate School of Medicine and Faculty of Medicine Kyoto University

  https://www.med.kyoto-u.ac.jp/en/research/field/doctoral_course/r-206

  Multiple System Atrophy (MSA) is one of the neurodegenerative diseases and is the most intractable diseases among the known rare diseases that cause various nervous system symptoms such as movement disorders and autonomic nervous system disorders. […] Although there are more than 10,000 patients with MSA in Japan, the pathogenesis of the disease has not yet been fully understood, and no curative treatment has been established. The Department of Therapeutics of Multiple System Atrophy aims to elucidate the pathogenesis of MSA and develop its treatment. […] We will elucidate the molecular mechanisms of multiple system atrophy (MSA) pathogenesis, create animal models, and search for biomarkers to establish early diagnostic methods.

• #67 Understanding Multiple System Atrophy— Could Genetics Lead the Way? – touchNEUROLOGY

  https://touchneurology.com/movement-disorders/journal-articles/understanding-multiple-system-atrophy-could-genetics-lead-the-way/

  Multiple system atrophy (MSA) is a progressive, adult-onset, neurodegenerative disorder characterized by parkinsonism, cerebellar ataxia, autonomic failure, and corticospinal tract dysfunction. […] There is still much unknown about this disease, but some of the recent advances made in MSA genetics may give important clues to understanding the pathogenesis and treatment of this disease. […] More recently there have been some advances in laboratory and translational research in MSA. In particular, genetics of MSA has been a recent topic of interest, and is opening new doors in the understanding of the pathogenesis of MSA. […] The pathogenesis of MSA remains an enigma, though it is becoming clear that genetic associations exist. Many mechanisms for the development and propagation of MSA have been postulated, including impaired elimination of -synuclein within the cell, mitochondrial dysfunction, direct toxicity of -synuclein, oxidative stress, and neuroinflammation. […] We are hopeful that genetic associations may give us further clues into the pathogenesis of MSA, as well as targets for therapeutic interventions.

• #68 Models of multiple system atrophy | Experimental & Molecular Medicine

  https://www.nature.com/articles/s12276-019-0346-8

  A failure to discard proteins through cellular degradation pathways may lead to the production of toxic aggregates that may incorporate into GCIs and cause oligodendrocyte dysfunction. […] The activation of astrocytes and microglia has been observed in the brains of MSA patients, as well as in those of transgenic models of MSA. […] The injection of GCI extract into the mouse brain causes localized microgliosis, as well as astrogliosis. […] In vitro and in vivo models have been developed to obtain a better understanding of MSA pathophysiology. […] MSA pathophysiology has been addressed at the cellular level through modified gene expression. […] The transgenic expression of the -synuclein gene under oligodendrocyte-specific promoters has been used to create mouse models of MSA. […] The accumulation of -synuclein in oligodendroglia has been found in all three oligodendrocyte-specific promoter-driven human -synuclein tg mice. However, each of these mice displayed distinct patterns of pathological changes that do not precisely replicate human MSA pathology. […] Recent studies have suggested that GCIs are generated through the transfer of -synuclein from neurons to oligodendrocytes.

• #69 ClinMed International Library

  https://clinmedjournals.org/articles/ijnn/ijnn-2-022.php?jid=ijnn

  Further research on the basic pathogenic mechanisms, the interplay of the disease process with various pathobiological and molecular changes, and the nature of possible genetic and environmental triggers that unmask its pathogenesis will be needed to develop optimal animal models, and to clarify the relations between the development of pathomorphology and clinical manifestations as a basis for early diagnosis and a disease-modifying treatment of this hitherto incurable devastating disorder.

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