TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport

Hongyi Wu, Loo Chien Wang, Belle M. Sow, Damien Leow, Jin Zhu, Kathryn M. Gallo, Kathleen Wilsbach, Roshni Gupta, Lyle W. Ostrow, Crystal J. J. Yeo, Radoslaw M. Sobota and Rong Li ()
Additional contact information
Hongyi Wu: National University of Singapore (NUS)
Loo Chien Wang: Technology and Research (A*STAR)
Belle M. Sow: National University of Singapore (NUS)
Damien Leow: National University of Singapore
Jin Zhu: National University of Singapore (NUS)
Kathryn M. Gallo: Johns Hopkins University
Kathleen Wilsbach: Johns Hopkins University
Roshni Gupta: National University of Singapore (NUS)
Lyle W. Ostrow: Johns Hopkins University
Crystal J. J. Yeo: Technology and Research (A*STAR)
Radoslaw M. Sobota: Technology and Research (A*STAR)
Rong Li: National University of Singapore (NUS)

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Protein aggregation plays key roles in age-related degenerative diseases, but how different proteins coalesce to form inclusions that vary in composition, morphology, molecular dynamics and confer physiological consequences is poorly understood. Here we employ a general reporter based on mutant Hsp104 to identify proteins forming aggregates in human cells under common proteotoxic stress. We identify over 300 proteins that form different inclusions containing subsets of aggregating proteins. In particular, TDP43, implicated in Amyotrophic Lateral Sclerosis (ALS), partitions dynamically between two distinct types of aggregates: stress granule and a previously unknown non-dynamic (solid-like) inclusion at the ER exit sites (ERES). TDP43-ERES co-aggregation is induced by diverse proteotoxic stresses and observed in the motor neurons of ALS patients. Such aggregation causes retention of secretory cargos at ERES and therefore delays ER-to-Golgi transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patients.

Date: 2024
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DOI: 10.1038/s41467-024-52706-7

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