Grant: CIHR Fellowship

The synucleinopathies are a group of neurodegenerative diseases that arise from the abnormal accumulation of the alpha-synuclein protein in the brain and include Parkinson disease, multiple system atrophy and dementia with Lewy bodies. Multiple system atrophy presents with autonomic failure and variable degree of parkinsonism, cerebellar ataxia and pyramidal dysfunction, while dementia with Lewy bodies is characterized by early dementia, visual hallucinations and parkinsonism. The underlying factors driving the development of these disorders remain largely unknown and, as such, there exists no disease-modifying treatment available to halt disease progression. Although these diseases were once thought of as being non-heritable, recent studies have suggested that genetic factors play a definite role in their development. Nonetheless, little is still known about the genetic determinants of these two disorders. Recent advances in genetic technologies offer an unprecedented opportunity to bridge this gap. The main objective of this research project is to gain further understanding of the genetic underpinnings of these diseases by leveraging new genetic techniques. This will be accomplished through a three-step approach. Firstly, cases of multiple system atrophy and dementia with Lewy bodies will be studied using cutting-edge genome sequencing technologies and bioinformatic tools to identify disease-causing mutations. Secondly, similar techniques will be used to study specific cell populations in the brain of deceased multiple system atrophy and dementia with Lewy bodies cases. Finally, genome-wide association studies will be performed on large cohorts of patients to look for genetic risk factors of these two disorders. This project is expected to provide new insights into the complex genetic architecture of multiple system atrophy and dementia with Lewy bodies, which may pave the way for the development of disease-modifying therapies for these yet incurable diseases.