Elucidating the Role of Alternative Polyadenylation in ALS and FTD
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Research Area
Aging
Grant Type
Fellowship
Year
2023
Abstract
With an aging population, neurodegenerative disorders contribute increasingly to our global health burden with no cure or effective treatments available. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two neurodegenerative disorders that are distinct in clinical presentation but share a common underlying feature – that an essential protein named TDP-43 builds up in clumps inside neurons and loses its normal function in processing RNA, an essential molecule that acts as a template for protein production. The loss of TDP-43 is considered as a key driver of ALS and FTD; however, the underlying mechanism is not fully understood.
An important function of TDP-43 is to regulate alternative polyadenylation to determine the length of the 3’ UTR, a region at the end of RNA that is important for determining protein abundance, location, and function. Profound changes in genes’ 3’ UTR lengths have been observed in patients. Thus, my goal is to systematically investigate 1) which genes have altered 3’ UTRs upon TDP-43 dysfunction, 2) why these changes occur, and 3) if and how these changes contribute to neurodegeneration. To effectively address these questions, I will use a multitude of approaches that include stem cell technology, genetic screens, and machine learning. I will also validate my findings in human patient tissues. Ultimately, this proposal will generate exciting new insights into disease mechanisms and establish novel ways to diagnose and treat these diseases.