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-Structure paper
Title | Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons. |
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Journal, issue, pages | EMBO Rep, Vol. 23, Issue 6, Page e53890, Year 2022 |
Publish date | Jun 7, 2022 |
Authors | 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 / |
PubMed 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 ...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. |
External links | EMBO Rep / PubMed:35438230 / PubMed Central |
Methods | EM (subtomogram averaging) / EM (tomography) |
Resolution | 20.0 Å |
Structure data | EMDB-32216: EMDB-32217: |
Source |
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