Journal Article

DZNE-2022-00611

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons.

Riemenschneider, H. (First author)DZNE* ; Guo, Q. ; Bader, J.Extern* ; Frottin, F. ; Farny, D.DZNE* ; Kleinberger, G.DZNE* ; Haass, C.DZNE* ; Mann, M. ; Hartl, F. U. ; Baumeister, W. ; Hipp, M. S. ; Meissner, F. ; Fernández-Busnadiego, R. ; Edbauer, D. (Last author)DZNE*

2022
Wiley Hoboken, NJ [u.a.]

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Please use a persistent id in citations: doi:10.15252/embr.202153890

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.

Keyword(s): Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; DNA-Binding Proteins: genetics (MeSH) ; DNA-Binding Proteins: metabolism (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: metabolism (MeSH) ; Humans (MeSH) ; Inclusion Bodies: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Peptide Fragments: genetics (MeSH) ; Peptide Fragments: metabolism (MeSH) ; Proteasome Endopeptidase Complex: metabolism (MeSH) ; ALS ; TDP-43 ; neurodegeneration ; phase separation ; proteasome

Note: (CC BY)

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Contributing Institute(s):

1. Cell Biology of Neurodegeneration (AG Edbauer)
2. Neuroproteomics (AG Lichtenthaler)
3. Translational Brain Research (AG Herms)
4. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Journal Article (Erratum/Correction) Riemenschneider, H. (First author)DZNE* ; Guo, Q. ; Bader, J. ; Frottin, F. ; Farny, D.DZNE* ; Kleinberger, G.DZNE* ; Haass, C.DZNE* ; Mann, M. ; Hartl, F. U. ; Baumeister, W. ; Hipp, M. S. ; Meissner, F. ; Fernández-Busnadiego, R. ; Edbauer, D. (Last author)DZNE*
Author Correction: Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons
EMBO reports 25(7), 3161 (2024) [10.1038/s44319-024-00163-0]2024   Files  Fulltext by Pubmed Central BibTeX | EndNote: XML, Text | RIS

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