Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

In: EMBO Reports, Vol. 23, No. 6, e53890, 2022.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Riemenschneider, H, Guo, Q, Bader, J, Frottin, F, Farny, D, Kleinberger, G, Haass, C, Mann, M, Hartl, FU, Baumeister, W, Hipp, MS, Meissner, F, Fernández-Busnadiego, R & Edbauer, D 2022, 'Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons', EMBO Reports, vol. 23, no. 6, e53890. https://doi.org/10.15252/embr.202153890

APA

Riemenschneider, H., Guo, Q., Bader, J., Frottin, F., Farny, D., Kleinberger, G., Haass, C., Mann, M., Hartl, F. U., Baumeister, W., Hipp, M. S., Meissner, F., Fernández-Busnadiego, R., & Edbauer, D. (2022). Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons. EMBO Reports, 23(6), [e53890]. https://doi.org/10.15252/embr.202153890

Vancouver

Riemenschneider H, Guo Q, Bader J, Frottin F, Farny D, Kleinberger G et al. Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons. EMBO Reports. 2022;23(6). e53890. https://doi.org/10.15252/embr.202153890

Author

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. / Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons. In: EMBO Reports. 2022 ; Vol. 23, No. 6.

Bibtex

@article{7b0699784cac4b209467a4604a9aeb78,
title = "Gel-like inclusions of C-terminal fragments of TDP-43 sequester stalled proteasomes in neurons",
abstract = "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.",
keywords = "Amyotrophic Lateral Sclerosis/genetics, DNA-Binding Proteins/genetics, Frontotemporal Dementia/genetics, Humans, Inclusion Bodies/metabolism, Neurons/metabolism, Peptide Fragments/genetics, Proteasome Endopeptidase Complex/metabolism",
author = "Henrick Riemenschneider and Qiang Guo and Jakob Bader and Fr{\'e}d{\'e}ric Frottin and Daniel Farny and Gernot Kleinberger and Christian Haass and Matthias Mann and Hartl, {F Ulrich} and Wolfgang Baumeister and Hipp, {Mark S} and Felix Meissner and Rub{\'e}n Fern{\'a}ndez-Busnadiego and Dieter Edbauer",
note = "{\textcopyright} 2022 The Authors. Published under the terms of the CC BY 4.0 license.",
year = "2022",
doi = "10.15252/embr.202153890",
language = "English",
volume = "23",
journal = "E M B O Reports",
issn = "1469-221X",
publisher = "Wiley-Blackwell",
number = "6",

}

RIS

TY - JOUR

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