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000163937 1001_ $$0P:(DE-2719)2812261$$aRiemenschneider, Henrick$$b0$$eFirst author$$udzne
000163937 245__ $$aGel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons.
000163937 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2022
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000163937 520__ $$aAggregation 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.
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000163937 650_7 $$2Other$$aALS
000163937 650_7 $$2Other$$aTDP-43
000163937 650_7 $$2Other$$aneurodegeneration
000163937 650_7 $$2Other$$aphase separation
000163937 650_7 $$2Other$$aproteasome
000163937 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000163937 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000163937 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000163937 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000163937 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000163937 650_2 $$2MeSH$$aFrontotemporal Dementia: metabolism
000163937 650_2 $$2MeSH$$aHumans
000163937 650_2 $$2MeSH$$aInclusion Bodies: metabolism
000163937 650_2 $$2MeSH$$aNeurons: metabolism
000163937 650_2 $$2MeSH$$aPeptide Fragments: genetics
000163937 650_2 $$2MeSH$$aPeptide Fragments: metabolism
000163937 650_2 $$2MeSH$$aProteasome Endopeptidase Complex: metabolism
000163937 7001_ $$00000-0003-3520-5439$$aGuo, Qiang$$b1
000163937 7001_ $$0P:(DE-2719)2812147$$aBader, Jakob$$b2$$udzne
000163937 7001_ $$00000-0002-2756-7838$$aFrottin, Frédéric$$b3
000163937 7001_ $$0P:(DE-2719)2812127$$aFarny, Daniel$$b4$$udzne
000163937 7001_ $$0P:(DE-2719)9000907$$aKleinberger, Gernot$$b5$$udzne
000163937 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b6$$udzne
000163937 7001_ $$00000-0003-1292-4799$$aMann, Matthias$$b7
000163937 7001_ $$00000-0002-7941-135X$$aHartl, F Ulrich$$b8
000163937 7001_ $$aBaumeister, Wolfgang$$b9
000163937 7001_ $$00000-0002-0497-3016$$aHipp, Mark S$$b10
000163937 7001_ $$00000-0003-1000-7989$$aMeissner, Felix$$b11
000163937 7001_ $$00000-0002-8366-7622$$aFernández-Busnadiego, Rubén$$b12
000163937 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b13$$eLast author$$udzne
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000163937 9201_ $$0I:(DE-2719)1110004$$kAG Edbauer$$lCell Biology of Neurodegeneration$$x0
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