%0 Journal Article
%A Riemenschneider, Henrick
%A Guo, Qiang
%A Bader, Jakob
%A Frottin, Frédéric
%A Farny, Daniel
%A Kleinberger, Gernot
%A Haass, Christian
%A Mann, Matthias
%A Hartl, F Ulrich
%A Baumeister, Wolfgang
%A Hipp, Mark S
%A Meissner, Felix
%A Fernández-Busnadiego, Rubén
%A Edbauer, Dieter
%T Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons.
%J EMBO reports
%V 23
%N 6
%@ 1469-221X
%C Hoboken, NJ [u.a.]
%I Wiley
%M DZNE-2022-00611
%P e53890
%D 2022
%Z (CC BY)
%X 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.
%K Amyotrophic Lateral Sclerosis: genetics
%K Amyotrophic Lateral Sclerosis: metabolism
%K DNA-Binding Proteins: genetics
%K DNA-Binding Proteins: metabolism
%K Frontotemporal Dementia: genetics
%K Frontotemporal Dementia: metabolism
%K Humans
%K Inclusion Bodies: metabolism
%K Neurons: metabolism
%K Peptide Fragments: genetics
%K Peptide Fragments: metabolism
%K Proteasome Endopeptidase Complex: metabolism
%K ALS (Other)
%K TDP-43 (Other)
%K neurodegeneration (Other)
%K phase separation (Other)
%K proteasome (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%2 pmc:PMC9171420
%$ pmid:35438230
%R 10.15252/embr.202153890
%U https://pub.dzne.de/record/163937