Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons

Henrick Riemenschneider, Qiang Guo, Jakob Bader, Frédéric Frottin, Daniel Farny, Gernot Kleinberger, Christian Haass, Matthias Mann, F. Ulrich Hartl, Wolfgang Baumeister, Mark S. Hipp, Felix Meissner, Rubén Fernández-Busnadiego*, Dieter Edbauer*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    Abstract

    Aggregation of the multifunctional RNA-binding protein TDP-43 defines large subgroups of amyotrophic lateral sclerosis and frontotemporal dementia and correlates with neurodegeneration in both diseases. In disease, characteristic C-terminal fragments of ~25 kDa ("TDP-25") accumulate in cytoplasmic inclusions. Here, we analyze gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics, and functional assays. In neurons, cytoplasmic TDP-25 inclusions are amorphous, and photobleaching experiments reveal gel-like biophysical properties that are less dynamic than nuclear TDP-43. Compared with full-length TDP-43, the TDP-25 interactome is depleted of low-complexity domain proteins. TDP-25 inclusions are enriched in 26S proteasomes adopting exclusively substrate-processing conformations, suggesting that inclusions sequester proteasomes, which are largely stalled and no longer undergo the cyclic conformational changes required for proteolytic activity. Reporter assays confirm that TDP-25 impairs proteostasis, and this inhibitory function is enhanced by ALS-causing TDP-43 mutations. These findings support a patho-physiological relevance of proteasome dysfunction in ALS/FTD.

    Original languageEnglish
    Article numbere53890
    Number of pages12
    JournalEmbo Reports
    Volume23
    DOIs
    Publication statusE-pub ahead of print - 19-Apr-2022

    Keywords

    • ALS
    • neurodegeneration
    • phase separation
    • proteasome
    • TDP-43

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