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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. M., Frottin, F., Farny, D., Kleinberger, G., et al. (2022). Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons. EMBO Reports, 23(6): e53890. doi:10.15252/embr.202153890.

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Riemenschneider, Henrick, Autor
Guo, Qiang1, Autor           
Bader, Jakob Maximilian2, Autor           
Frottin, Frederic3, Autor           
Farny, Daniel, Autor
Kleinberger, Gernot, Autor
Haass, Christian, Autor
Mann, Matthias2, Autor           
Hartl, F. Ulrich3, Autor           
Baumeister, Wolfgang1, Autor           
Hipp, Mark S.3, Autor           
Meissner, Felix2, Autor           
Fernandez-Busnadiego, Ruben1, Autor           
Edbauer, Dieter, Autor
Affiliations:
1Baumeister, Wolfgang / Molecular Structural Biology, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565142              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              
3Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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Schlagwörter: FRONTOTEMPORAL LOBAR DEGENERATION; PHASE-SEPARATION; PROTEINS; ALS; MUTATIONS; PATHOLOGY; PROTEOME; GRANULES; LOCALIZATION; COMPLEXESBiochemistry & Molecular Biology; Cell Biology; ALS; neurodegeneration; phase separation; proteasome; TDP-43;
 Zusammenfassung: Aggregation of the multifunctional RNA-binding protein TDP-43 defines large subgroups of amyotrophic lateral sclerosis and fronto-temporal dementia and correlates with neurodegeneration in both diseases. In disease, characteristic C-terminal fragments of similar to 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 265 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 pathophysiological relevance of proteasome dysfunction in ALS/FTD.

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Sprache(n): eng - English
 Datum: 2022-06-07
 Publikationsstatus: Erschienen
 Seiten: 12
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: ISI: 000783461500001
DOI: 10.15252/embr.202153890
 Art des Abschluß: -

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Titel: EMBO Reports
  Andere : EMBO Rep.
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: Oxford, UK : Published for EMBO by Oxford University Press
Seiten: - Band / Heft: 23 (6) Artikelnummer: e53890 Start- / Endseite: - Identifikator: ISSN: 1469-221X
CoNE: https://pure.mpg.de/cone/journals/resource/110978984569661