Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons
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Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons. / Riemenschneider, Henrick; Guo, Qiang; Bader, Jakob; Frottin, Frédéric; Farny, Daniel; Kleinberger, Gernot; Haass, Christian; Mann, Matthias; Hartl, F Ulrich; Baumeister, Wolfgang; Hipp, Mark S; Meissner, Felix; Fernández-Busnadiego, Rubén; Edbauer, Dieter.
I: EMBO Reports, Bind 23, Nr. 6, e53890, 2022.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons
AU - Riemenschneider, Henrick
AU - Guo, Qiang
AU - Bader, Jakob
AU - Frottin, Frédéric
AU - Farny, Daniel
AU - Kleinberger, Gernot
AU - Haass, Christian
AU - Mann, Matthias
AU - Hartl, F Ulrich
AU - Baumeister, Wolfgang
AU - Hipp, Mark S
AU - Meissner, Felix
AU - Fernández-Busnadiego, Rubén
AU - Edbauer, Dieter
N1 - © 2022 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2022
Y1 - 2022
N2 - Aggregation 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.
AB - Aggregation 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.
KW - Amyotrophic Lateral Sclerosis/genetics
KW - DNA-Binding Proteins/genetics
KW - Frontotemporal Dementia/genetics
KW - Humans
KW - Inclusion Bodies/metabolism
KW - Neurons/metabolism
KW - Peptide Fragments/genetics
KW - Proteasome Endopeptidase Complex/metabolism
U2 - 10.15252/embr.202153890
DO - 10.15252/embr.202153890
M3 - Journal article
C2 - 35438230
VL - 23
JO - E M B O Reports
JF - E M B O Reports
SN - 1469-221X
IS - 6
M1 - e53890
ER -
ID: 331591188