Targeting the VCP-binding motif of ataxin-3 improves phenotypes in Drosophila models of Spinocerebellar Ataxia Type 3.
AAA ATPase
Ataxia
Ataxin-3
Deubiquitinase
Drosophila
Machado-Joseph Disease
Neurodegeneration
Polyglutamine
Spinocerebellar Ataxia Type 3
VCP/p97
Journal
Neurobiology of disease
ISSN: 1095-953X
Titre abrégé: Neurobiol Dis
Pays: United States
ID NLM: 9500169
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
30
06
2021
revised:
23
08
2021
accepted:
21
09
2021
pubmed:
27
9
2021
medline:
29
3
2022
entrez:
26
9
2021
Statut:
ppublish
Résumé
Of the family of polyglutamine (polyQ) neurodegenerative diseases, Spinocerebellar Ataxia Type 3 (SCA3) is the most common. Like other polyQ diseases, SCA3 stems from abnormal expansions in the CAG triplet repeat of its disease gene resulting in elongated polyQ repeats within its protein, ataxin-3. Various ataxin-3 protein domains contribute to its toxicity, including the valosin-containing protein (VCP)-binding motif (VBM). We previously reported that VCP, a homo-hexameric protein, enhances pathogenic ataxin-3 aggregation and exacerbates its toxicity. These findings led us to explore the impact of targeting the SCA3 protein by utilizing a decoy protein comprising the N-terminus of VCP (N-VCP) that binds ataxin-3's VBM. The notion was that N-VCP would reduce binding of ataxin-3 to VCP, decreasing its aggregation and toxicity. We found that expression of N-VCP in Drosophila melanogaster models of SCA3 ameliorated various phenotypes, coincident with reduced ataxin-3 aggregation. This protective effect was specific to pathogenic ataxin-3 and depended on its VBM. Increasing the amount of N-VCP resulted in further phenotype improvement. Our work highlights the protective potential of targeting the VCP-ataxin-3 interaction in SCA3, a key finding in the search for therapeutic opportunities for this incurable disorder.
Identifiants
pubmed: 34563642
pii: S0969-9961(21)00265-5
doi: 10.1016/j.nbd.2021.105516
pmc: PMC8693084
mid: NIHMS1762179
pii:
doi:
Substances chimiques
Ataxin-3
EC 3.4.19.12
Valosin Containing Protein
EC 3.6.4.6
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
105516Subventions
Organisme : NINDS NIH HHS
ID : R01 NS086778
Pays : United States
Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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