Journal Article

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

Zhu, Jin, Wu, Hongyi, Li, Rong, Wang, Loo Chien, Sow, Belle M., Sobota, Radoslaw M., Gallo, Kathryn M., Gupta, Roshni, Leow, Damien, Wilsbach, Kathleen, Ostrow, Lyle W., Yeo, Crystal J. J.

2024

Overview

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. Protein aggregation has been implicated in several neurodegenerative diseases. Here, Wu et al. utilized a general aggregate reporter to identify aggregation-prone proteins and discover that TDP43 aggregates at ER-exit sites (ERES) under proteotoxic stress and impairs ER-to-Golgi transport, linking TDP43 aggregation and ER dysfunction.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 14/19 / 631/378/1689/1285 / 631/80/304 / 631/80/313/1463 / 631/80/470/2284 / Age / Aggregates / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Amyotrophic Lateral Sclerosis - pathology / Axonal transport / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Endoplasmic Reticulum - metabolism / Golgi Apparatus - metabolism / HEK293 Cells / HeLa Cells / Humanities and Social Sciences / Humans / Inclusions / Molecular dynamics / Motor neurons / Motor Neurons - metabolism / multidisciplinary / Neurodegenerative diseases / Protein Aggregates / Protein composition / Protein interaction / Protein Transport / Proteins / Science / Science (multidisciplinary)