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

Author

Listed:
  • 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
    Temple University)

  • Kathleen Wilsbach

    (Johns Hopkins University
    Temple University)

  • Roshni Gupta

    (National University of Singapore (NUS))

  • Lyle W. Ostrow

    (Johns Hopkins University
    Temple University)

  • Crystal J. J. Yeo

    (Technology and Research (A*STAR)
    National Neuroscience Institute
    Duke-NUS Medical School
    Nanyang Technological University)

  • Radoslaw M. Sobota

    (Technology and Research (A*STAR))

  • Rong Li

    (National University of Singapore (NUS)
    National University of Singapore)

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.

Suggested Citation

  • 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 & Rong Li, 2024. "TDP43 aggregation at ER-exit sites impairs ER-to-Golgi transport," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52706-7
    DOI: 10.1038/s41467-024-52706-7
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    References listed on IDEAS

    as
    1. Amanda M. Gleixner & Brandie Morris Verdone & Charlton G. Otte & Eric N. Anderson & Nandini Ramesh & Olivia R. Shapiro & Jenna R. Gale & Jocelyn C. Mauna & Jacob R. Mann & Katie E. Copley & Elizabeth , 2022. "NUP62 localizes to ALS/FTLD pathological assemblies and contributes to TDP-43 insolubility," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Itika Saha & Patricia Yuste-Checa & Miguel Silva Padilha & Qiang Guo & Roman Körner & Hauke Holthusen & Victoria A. Trinkaus & Irina Dudanova & Rubén Fernández-Busnadiego & Wolfgang Baumeister & David, 2023. "The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Benedetta Bolognesi & Andre J. Faure & Mireia Seuma & Jörn M. Schmiedel & Gian Gaetano Tartaglia & Ben Lehner, 2019. "The mutational landscape of a prion-like domain," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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