Riemenschneider H, Guo Q, Bader J, Frottin F, Farny D, Kleinberger G, Haass C, Mann M, Hartl FU, Baumeister W, Hipp MS, Meissner F, Fernandez-Busnadiego R, Edbauer D
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.