Nuclear inclusions of pathogenic ataxin-1 induce oxidative stress and perturb the protein synthesis machinery.
Ataxin-1
Oxidative stress
Polyglutamine
Protein network
Ribosome
Sleeping beauty transposon
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
31
10
2019
revised:
29
01
2020
accepted:
06
02
2020
pubmed:
8
3
2020
medline:
22
6
2021
entrez:
8
3
2020
Statut:
ppublish
Résumé
Spinocerebellar ataxia type-1 (SCA1) is caused by an abnormally expanded polyglutamine (polyQ) tract in ataxin-1. These expansions are responsible for protein misfolding and self-assembly into intranuclear inclusion bodies (IIBs) that are somehow linked to neuronal death. However, owing to lack of a suitable cellular model, the downstream consequences of IIB formation are yet to be resolved. Here, we describe a nuclear protein aggregation model of pathogenic human ataxin-1 and characterize IIB effects. Using an inducible Sleeping Beauty transposon system, we overexpressed the ATXN1(Q82) gene in human mesenchymal stem cells that are resistant to the early cytotoxic effects caused by the expression of the mutant protein. We characterized the structure and the protein composition of insoluble polyQ IIBs which gradually occupy the nuclei and are responsible for the generation of reactive oxygen species. In response to their formation, our transcriptome analysis reveals a cerebellum-specific perturbed protein interaction network, primarily affecting protein synthesis. We propose that insoluble polyQ IIBs cause oxidative and nucleolar stress and affect the assembly of the ribosome by capturing or down-regulating essential components. The inducible cell system can be utilized to decipher the cellular consequences of polyQ protein aggregation. Our strategy provides a broadly applicable methodology for studying polyQ diseases.
Identifiants
pubmed: 32145456
pii: S2213-2317(19)31294-7
doi: 10.1016/j.redox.2020.101458
pmc: PMC7058924
pii:
doi:
Substances chimiques
Ataxin-1
0
Nerve Tissue Proteins
0
Nuclear Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101458Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare no commercial or financial conflict of interest.
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