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Gel-like inclusions of C-terminal fragments of TDP-43 sequester and inhibit proteasomes in neurons

By Henrick Riemenschneider, Qiang Guo, Jakob Bader, Frederic Frottin, Daniel Farny, Gernot Kleinberger, Christian Haass, Matthias Mann, F. Ulrich Hartl, Wolfgang Baumeister, Mark S Hipp, Felix Meissner, Ruben Fernandez-Busnadiego, Dieter Edbauer

Posted 16 Mar 2021
bioRxiv DOI: 10.1101/2021.03.15.435268

TDP-43 inclusions enriched in C-terminal fragments of ~25kDa ("TDP-25") are associated with neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we analyzed gain-of-function mechanisms of TDP-25 combining cryo-electron tomography, proteomics and functional assays. TDP-25 inclusions are amorphous with gel-like biophysical properties and sequester proteasomes adopting exclusively substrate-processing conformations. This leads to proteostasis impairment, further enhanced by pathogenic mutations. These findings bolster the importance of proteasome dysfunction in ALS/FTD.

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