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

ABSTRACT: TDP-43 inclusions enriched in C-terminal terminal fragments of ~25 kDa ("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. We show that TDP-25 inclusions are amorphous with gel-like properties. Inclusions 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.

INSTRUMENT(S):

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Brain, Hippocampal Neuron

DISEASE(S): Amyotrophic Lateral Sclerosis

SUBMITTER: Mario Oroshi  

LAB HEAD: Matthias Mann

PROVIDER: PXD024358 | Pride | 2022-04-14

REPOSITORIES: Pride