Four new genetic risk factors for MSA have been identified

Four new genetic risk factors for MSA have been identified

A study recently published in the journal Neuron succeeded in identifying four new genetic risk factors for multiple system atrophy (MSA). For this purpose, the entire genome of people with MSA was examined in detail – this was made possible by the collaboration of more than 20 institutions worldwide – including experts from the Neurology Clinic of the University of Innsbruck.

MSA is an adult-onset, sporadic disorder that, along with Parkinson’s disease and Lewy body dementia, is classified as a “synucleinopathy” because one of its hallmarks is the abnormal formation of the α-synuclein protein. Neurodegenerative disease associated with autonomic failures, ataxia, and parkinsonism. The disease is so rare, occurs infrequently, and its symptoms vary from case to case, MSA is still poorly understood, unlike Parkinson’s disease and Lewy body dementia*.

Largest genome sequencing database for MSA

To fill this gap in understanding of MSA, Sonja W. The research team led by Scholes created the largest genome sequencing database for MSA. together till date. Sonja Scholz studied medicine in Innsbruck and wrote her dissertation on MSA under the supervision of globally recognized MSA expert Gregor Wenning, who died a few months ago.
Collecting the complete genomes of 888 people of European descent with MSA required an international collaboration with institutions from the US and Europe, including the contribution of the Innsbruck MSA group at the Department of Neurobiology, founded and led by Wenning.

The collected data were finally compared with the genomes of 7,128 control subjects to better understand the genetic basis of MSA.

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Caption: The Innsbruck MSA team, from left: Klaus Seppi, Viktoria Sidoroff, Susanne Doer, Florian Kriesmer, Alessandra Fanciulli and Nadia Stefanova. (Part of the team, but not pictured: Fabian Lees and Gregor K. Wenning). © Benjamin Tejagam

The team used modern and sophisticated genome-wide analysis techniques to examine more than nine million different genetic variants in this database. Finally, four new risk loci for MSA were identified. The researchers were also able to highlight specific genes associated with increased susceptibility to MSA.

However, this genetic analysis is only a first step. To better understand the effects of gene mutations on MSA, the researchers also performed a transcriptome analysis. This made it possible to detect changes in mRNA, the mechanisms by which proteins are produced from the human genome (DNA) template. The analysis showed the effects of genetic mutations associated with MSA on specific cell types, including neurons and oligodendrocytes, which are cells that support cellular communication in the brain. One of the most important findings of this study is that a defect in oligodendrocytes may be a central driver of MSA—a finding that supports the prevailing hypothesis about the origin of this neurological disorder.

These results are only the beginning of uncovering the causes of MSA. One of the limitations of this study is that it should be replicated in different MSA genomes. However, due to the rarity of the disease, which is an obstacle to support further research into MSA and its genetic basis, Scholz and his team are making their genetic data freely available to the research community. This approach to open data sharing follows the group’s political self-image, which has already been used in another large-scale analysis of Lewy body dementia and frontotemporal dementia. It is hoped that by publishing these detailed genomic and transcriptomic analyses, further research can build on these results and advance the goal of developing targeted therapies for MSA.

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(Innsbruck, June 13, 2024, text: free translated from English press release from D. Heidegger/NINDS, images: Innsbruck Neurobiology Unit, Benjamin Dejagum)


Chia R. and many others. “Gene sequence analyzes identify a new risk locus for multiple system atrophy.” Neurology. May 2, 2024.

*) Stepanova N, Wenning GK. “Multiple system atrophy: at the crossroads of cellular, molecular, and genetic mechanisms.” Nat Rev Neurosci. 2023, Jun;24(6):334-346.

**) Department of Neurology At the University Clinic of Neurology

The research project of the Department of Neurobiology (INBU, director: Nadia Stefanova) focuses on multiple system atrophy (MSA), a neurodegenerative disease (alpha-synucleinopathy) associated with autonomic failures, ataxia and parkinsonism. Over the years, the INBU team has made important contributions to key areas of MSA research, including disease mechanisms and therapeutic target discovery, clinical presentation, and diagnostic tools. The Department of Neurobiology has two core competencies: preclinical and clinical.

The pre-clinical research program of the Laboratory for Translational Neurodegeneration Research (Head: Nadia Stefanova) focuses on understanding the causes and disease mechanisms, early discovery of target molecules and disease modification in MSA and other alpha-synucleinopathies. The Clinical Research Program at the Dysautonomia Center (Director: Alessandra Fanciulli) focuses on early identification and development of personalized care plans for people living with MSA and other autonomic nervous system disorders. The Department of Neurobiology trains medical students, master’s and doctoral students and postdocs, national and international visiting scientists in translational neuroscience and offers a dynamic international research environment, collaborative approach and expertise in translational skills.

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