There are many examples where the study of rare disease has fundamentally changed our understanding of common diseases with similar phenotypic characteristics. This is true to a large extent because the rare disease represents a much clearer lens by which to understand the mechanisms of the disorder. This grant proposal focuses on the investigation of multiple system atrophy (MSA), a rare but severe neurodegenerative synucleinopathy with adult onset characterized by autonomic dysfunction with parkinsonism and/or cerebellar symptoms. Of specific interest in MSA are the oligodendroglial and neuronal cytoplasmic inclusions (GCIs and NCIs) formed by fibrillar alpha-synuclein (a-SYN) proteins although the pathogenic mechanisms driving these accumulations are unclear. Currently, there are no disease preventing or modifying treatments for MSA, and a crucial need for research to identify pathways that can be targeted for therapy. Little research has been done to understand the etiology of this disease especially in the area of modern genomic sequencing even though such an approach has revolutionized the way rare childhood disorders are investigated. Our first goal is to use family-based genomics to uncover rare genetic variants associated with MSA. We will perform genomic sequencing on quads of MSA patients, parents, and one unaffected sibling. Identified genetic variants will be characterized in vitro by using CRISPR-Cas9 engineering of existing cell-lines. Our second goal is to identify the pathogenic mechanisms important to MSA a-SYN accumulation, by combining laser capture microdissection and next generation RNA-Seq in neuropath-confirmed MSA brains and matched controls. Both of these aims are designed to identify underlying disease mechanisms and key targets that could be exploited as potential future therapeutic options. Our findings may shed additional light on the mechanisms of disease in more common synucleinopathies like Parkinson's disease and Lewy Body Dementia.

Public Health Relevance

This proposal focuses on the better understanding of the potential mechanisms of a rare neurological disease with adult onset, known as multiple system atrophy (MSA). We propose to study the genomics of the disease and use cell culture to understand the function. Identification of these mechanisms can be important to identify therapeutic targets for both MSA, and similar diseases like Parkinson's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Sieber, Beth-Anne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Translational Genomics Research Institute
United States
Zip Code
Walsh, Ryan R; Krismer, Florian; Galpern, Wendy R et al. (2018) Recommendations of the Global Multiple System Atrophy Research Roadmap Meeting. Neurology 90:74-82
Caselli, Richard J; Beach, Thomas G; Knopman, David S et al. (2017) Alzheimer Disease: Scientific Breakthroughs and Translational Challenges. Mayo Clin Proc 92:978-994