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

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.

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Publication Details

Journal
Nature Communications
Published
2024-10-18
DOI
https://doi.org/10.1038/s41467-024-52706-7
Citations
8
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article
Field-Weighted Citation Impact
2.61

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article

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

Lyle W. Ostrow, Jin Zhu, Kathleen Wilsbach, Radoslaw M. Sobota et al.
8 citations
Nature Communications
Endoplasmic Reticulum Stress and Disease
2.61
article

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

Lyle W. Ostrow, Jin Zhu, Kathleen Wilsbach, Radoslaw M. Sobota, Crystal Jing Jing Yeo, Belle M. Sow, Roshni Gupta, Hongyi Wu, Loo Chien Wang, Damien Meng-Kiat Leow, Kathryn M. Gallo, Rong Li
article en
8 citations

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.

Nature CommunicationsVol. 15(1)
Northwestern University (US), Agency for Science, Technology and Research (SG), Johns Hopkins University (US), National University of Singapore (SG), Nanyang Technological University (SG), University of Aberdeen (GB), Johns Hopkins Medicine (US), Duke-NUS Medical School (SG), National Neuroscience Institute (SG), Institute of Molecular and Cell Biology (SG), Temple University (US)
National Research Foundation Singapore, Ministry of Education - Singapore, Singapore Institute of Manufacturing Technology
Openalex Percentile: Top 10%
Endoplasmic Reticulum Stress and Disease
2.61
DOIOpen Access PDFOpenAlex
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