Gel‐like inclusions of C‐terminal fragments of TDP‐43 sequester stalled proteasomes in neurons
2022 | journal article; research paper. A publication with affiliation to the University of Göttingen.
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Gel‐like inclusions of C‐terminal fragments of TDP‐43 sequester stalled proteasomes in neurons
Riemenschneider, H.; Guo, Q.; Bader, J.; Frottin, F.; Farny, D.; Kleinberger, G. & Haass, C. et al. (2022)
EMBO Reports,. DOI: https://doi.org/10.15252/embr.202153890
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Details
- Authors
- Riemenschneider, Henrick; Guo, Qiang; Bader, Jakob; Frottin, Frédéric; Farny, Daniel; Kleinberger, Gernot; Haass, Christian; Mann, Matthias; Hartl, F. Ulrich; Baumeister, Wolfgang; Edbauer, Dieter
- 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.
- Issue Date
- 2022
- Journal
- EMBO Reports
- Project
- EXC 2067: Multiscale Bioimaging
- Working Group
- RG Fernández-Busnadiego (Structural Cell Biology)
- ISSN
- 1469-221X
- eISSN
- 1469-3178
- Language
- English