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Multiple system atrophy: at the crossroads of cellular, molecular and genetic mechanisms

Nature Reviews Neuroscience volume 24, pages 334–346 (2023)Cite this article

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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 currently lacking. 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 genetic and neuropathological studies as well as studies in experimental models of MSA have indicated the involvement of genetic and epigenetic changes; α-synuclein misfolding, aggregation and spreading; and α-synuclein strain 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 its impact on biomarker discovery and treatment target definitions.

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Fig. 1: Experimental models of multiple system atrophy-like α-synucleinopathy.
Fig. 2: Multifactorial dysfunction of oligodendroglia in multiple system atrophy — putative pathogenic cascades.
Fig. 3: Current understanding of the primary oligodendrogliopathy underlying the neurodegenerative process in multiple system atrophy.
Fig. 4: Putative initiators of multiple system atrophy.

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  1. Division of Neurobiology, Department of Neurology, Medical University Innsbruck, Innsbruck, Austria

    Nadia Stefanova & Gregor K. Wenning

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N.S. reports consultancy fees from Inhibikase Therapeutics and Astellas Pharma and research grants from the Austrian Science Fund (FWF), Alterity Therapeutics and the US MSA Coalition. G.K.W. reports consultancy and lecture fees from Biohaven, Inhibikase, Ono and Takeda and research grants from the Austrian Science Fund (FWF), the Austrian National Bank, the US MSA Coalition, Parkinson Funds Austria and International Parkinson and Movement Disorder Society outside the submitted work.

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Stefanova, N., Wenning, G.K. Multiple system atrophy: at the crossroads of cellular, molecular and genetic mechanisms. Nat Rev Neurosci 24, 334–346 (2023). https://doi.org/10.1038/s41583-023-00697-7

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