Characterizing Genetic and Therapeutic Modulators of TDP-43 Aggregation

Marilyn Ngo, MPH - Final Dissertation Defense - HUGEN PhD Candidate Department of Human Genetics Doctoral Candidate, Marilyn Ngo, MPH, will defend the following dissertation on “Characterizing Genetic and Therapeutic Modulators of TDP-43 Aggregation” COMMITTEE CHAIR: Christopher J. Donnelly, PhD Committee Members: Julia K. Kofler, MDRyan L. Minster, PhD, MSISZsolt Urban, PhD ABSTRACT: TDP-43 is a DNA/RNA binding protein involved in RNA splicing, metabolism, and trafficking. TDP-43 is mislocalized from the nucleus to the cytoplasm where it forms pathological insoluble inclusions through liquid-liquid phase separation (LLPS) in several neurodegenerative diseases including Limbic-predominant, Age-related TDP-43 Encephalopathy (LATE), Amyotrophic Lateral Sclerosis (ALS), and Frontotemporal Lobar Degeneration (FTLD-TDP). There are currently 3 FDA-approved therapeutics for ALS and none for FTLD or LATE. Current treatments available for patients extend survival time and improve quality of life; however, none are curative or target underlying pathological processes of TDP-43 proteinopathies. To address this, we performed a blinded, two-platform phenotypic screen to identify potential small molecule inhibitors of TDP-43 aggregation. Using a biochemical LLPS assay and an optogenetics-based imaging screen we tested 471 compounds and converged upon a lead compound candidate that lowered both TDP-43 aggregate size and count by ~20%. By better understanding the genetic landscape of these complex diseases, we may be able to further develop targeted therapeutics and enhance precision medicine. To identify genetic modifiers of TDP-43 proteinopathies, we performed a genome-wide association study looking for modulators of TDP-43 aggregation on a postmortem cohort of moderate to severe Alzheimer’s disease (AD) cases with variable presence of concurrent LATE pathology and identified a genome-wide significant signal in SCY1 Like Pseudokinase