TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport
Year: 2024
Type: article
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 employed a general reporter based on mutant Hsp104 to identify proteins forming aggregates in human cells under common proteotoxic stress. Over 300 proteins were identified, forming 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 solid inclusion at the ER exit sites (ERES). TDP43-ERES coaggregation 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 delayed ER-to-Golgi transport, providing a link between TDP43 aggregation and compromised cellular function in ALS patients.
Source: Nature Communications
Institutions: National University of Singapore, Mechanobiology Institute, Agency for Science, Technology and Research, Institute of Molecular and Cell Biology, Johns Hopkins University, Temple University, Northwestern University, Nanyang Technological University, University of Aberdeen, Duke-NUS Medical School, National Neuroscience Institute
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: G1213292995, G3836447269
OpenAlex ID: W4403524853