Project 455055

Movement disorders are a subcategory of neurodegenerative diseases caused by progressive deterioration of brain cells and resulting in muscle weakness, abnormal movements, and/or tremors. The disorders may be rarer, but fatal, such as amyotrophic lateral sclerosis (ALS) or more common such as essential tremor (ET), which affects up to 5% of older adults. Currently, these conditions lack treatment options and much remains to be understood regarding an individual's genetic susceptibility to the diseases. Here, I aim to use large DNA sequencing datasets to identify new movement disorder-associated genes, by comparing DNA mutation frequencies in disease cases versus healthy control samples. To study ALS, I will apply rigorous statistical approaches to the two largest DNA sequencing datasets of ALS patients. In addition to taking an agnostic approach looking at all genes in the genome, I will investigate sets of genes known to contribute to molecular pathways associated with ALS. Further, I will use our understanding of which regions of genes may have greater functional implications when mutated to guide my analyses. All novel genetic findings will be validated with cell-based experiments. We are also currently initiating a consortium to create the largest DNA sequencing datasets yet available for ET by partnering with international research collaborators that also study patients with the disorder. I will take a leading role in this initiative and, following the DNA sequencing, I will apply similar analysis methods as described above in regards to ALS to identify and validate new genes contributing to the risk of ET. The results of this study will provide further insights into what may be causing movement disorders on a molecular level, allowing for the identification of new treatment targets and genetic-sequencing-based early diagnostic and risk assessment tools. It is our goal to improve the diagnosis, prognosis, and outcomes for individuals facing movement disorders.