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, MD
• Ryan L. Minster, PhD, MSIS
• Zsolt 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 3 (SCYL3; rs73026223). This variant was associated with increased severity of TDP-43 pathology in a 3-tiered staging system (p=3.61E-08) and correlated with decreased SCYL3 expression based on GTEx data. Functional studies demonstrated that knocking down SCYL3 expression promotes aberrant TDP-43 LLPS, suggesting a role for SCYL3 in TDP-43 pathology.

          To further explore the mechanisms by which SCYL3 may influence TDP-43 pathobiology, we characterized the SCYL3-dependent transcriptomic landscape and protein interactome using RNA sequencing in human iPSC-derived motor neurons and APEX2-based proximity labeling. These approaches implicate cytoskeletal organization and ROCK-associated signaling networks as candidate pathways through which SCYL3 may influence neuronal structure and signaling. This work highlights how SCYL3 is a potential genetic modifier that may contribute to selective neuronal vulnerability in TDP-43 proteinopathies.

IN-PERSON EVENT - ALL WELCOME