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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): Q Exactive HF-X

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

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	20190606_QX3_JaBa_SA_LC15_col1-50cm_main1_IP6-1_26xIP1D1S2fM1_blue_AD117_A_sample01.raw	Raw
	20190606_QX3_JaBa_SA_LC15_col1-50cm_main1_IP6-1_26xIP1D1S2fM1_blue_AD117_B_sample02.raw	Raw
	20190606_QX3_JaBa_SA_LC15_col1-50cm_main1_IP6-1_26xIP1D1S2fM1_blue_AD117_C_sample03.raw	Raw
	20190606_QX3_JaBa_SA_LC15_col1-50cm_main1_IP6-1_26xIP1D1S2fM1_blue_AD117_D_sample04.raw	Raw
	20190606_QX3_JaBa_SA_LC15_col1-50cm_main1_IP6-1_26xIP1D1S2fM1_blue_AD117_E_sample05.raw	Raw

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