Amyloidogenic oligomers derived from TDP-43 LCD promote the condensation and phosphorylation of TDP-43
Year: 2025
Type: article
Abstract: both classical amyloidogenesis and phase separation-mediated mechanisms, the role of amyloidogenic oligomers in modulating TDP-43 condensation remains unclear. Herein, we employ a reverse micelle method to prepare uniform oligomers derived from the low-complexity domain of TDP-43, termed D1core oligomers. These amyloidogenic oligomers are toxic, potently induce phase separation of recombinant TDP-43 C-terminal domains, and promote phosphorylation of cytosolic TDP-43 condensates in cells. Compared to monomeric or fibrillar forms, D1core oligomers uniquely enhance the condensation propensity of wild-type TDP-43 and further potentiate aggregation of the ALS-associated A315T mutant. Live-cell studies using fluorescence recovery after photobleaching reveal that oligomer-induced condensates are modulated by HSP70, which preserves their liquid-like properties. These findings provide new insights into the interplay between TDP-43 oligomers, phase separation, and aggregation, advancing our understanding of ALS-related proteinopathy.
Source: Chemical Science
DOI: 10.1039/d5sc05433h
Authors: Bryan Po-Wen Chen, Chi-Chang Lee, Ruei-Yu He, An-Chi Huang, Jie-rong Huang, Jerry Chun Chung Chan, Joseph Jen-Tse Huang
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
Awards: G1028360599, Protein-Protein Interactions Associated with Oligomeric Aggregates of Beta Amyloid Peptides, G1455492379, To Elucidate the Impacts of Fus Protein Physical States on Its Cellular Functions and Diseases with Photocontrollable Platform( II ), G3965122030, G7316924442, G7731086574, To Elucidate the Impacts of Fus Protein Physical States on Its Cellular Functions and Diseases with Photocontrollable Platform( I )
OpenAlex ID: W4416199588