Abstract
Multiple system atrophy (MSA) is a rare oligodendroglial α-synucleinopathy characterized by neurodegeneration in striatonigral and olivopontocerebellar regions and autonomic brain centres. It causes complex cumulative motor and non-motor disability with fast progression and effective therapy is currentlylacking. The difficulties in the diagnosis and treatment of MSA are largely related to the incomplete understanding of the pathogenesis of the disease. The MSA pathogenic landscape is complex, and converging findings from geneticand neuropathological studiesas well as studies in experimental models of MSA have indicated the involvement ofgenetic and epigenetic changes; α-synuclein misfolding, aggregationand spreading; and α-synucleinstrain specificity. These studies also indicate the involvement of myelin and iron dyshomeostasis, neuroinflammation, mitochondrial dysfunction and other cell-specific aspects that are relevant to the fast progression of MSA. In this Review, we discuss these findings and emphasize the implications of the complexity of the multifactorial pathogenic cascade for future translational research and itsimpact on biomarker discovery and treatment target definitions.
Published Version
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