Roles of TDP-43 domains in RNA-free phase separation

• Main Author: Sim, Dynn
• Other Authors: Choe Young Jun
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2022
• Subjects: Science::Biological sciences::Molecular biology
• Online Access: https://hdl.handle.net/10356/156887
• Institution: Nanyang Technological University

TAR-DNA-binding protein (TDP-43) has remained the central focus of research into Amyotrophic Lateral Sclerosis (ALS) since its discovery as the primary component of pathological inclusions in ALS patients. RNA-deficient TDP-43 was shown to demix into spherical shell-like condensates, which was suggested to be the precursor of the cytoplasmic aggregates. In this study, I investigated how each TDP-43 domain contributes to the formation of TDP-43 spherical shells. In particular, the role of the RNA recognition motifs (RRMs) during the shell-like phase separation was thoroughly examined. Self-association of TDP-43 via NTD (N-terminal domain) appeared to be crucial for the aggregation or phase separation of wild-type and RNA-binding deficient TDP-43. Notably, neither the NTD nor the LCD (low complexity domain) could phase separate when they were separate from each other. I also examined if the NTD and the LCD are transferrable to other proteins. This study will give insights into the condensation and aggregation mechanism of pathologic TDP-43.