Knockout or inhibition of USP30 protects dopaminergic neurons in a Parkinson's disease mouse model.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
13 11 2023
13 11 2023
Historique:
received:
16
12
2022
accepted:
24
10
2023
medline:
15
11
2023
pubmed:
14
11
2023
entrez:
13
11
2023
Statut:
epublish
Résumé
Mutations in SNCA, the gene encoding α-synuclein (αSyn), cause familial Parkinson's disease (PD) and aberrant αSyn is a key pathological hallmark of idiopathic PD. This α-synucleinopathy leads to mitochondrial dysfunction, which may drive dopaminergic neurodegeneration. PARKIN and PINK1, mutated in autosomal recessive PD, regulate the preferential autophagic clearance of dysfunctional mitochondria ("mitophagy") by inducing ubiquitylation of mitochondrial proteins, a process counteracted by deubiquitylation via USP30. Here we show that loss of USP30 in Usp30 knockout mice protects against behavioral deficits and leads to increased mitophagy, decreased phospho-S129 αSyn, and attenuation of SN dopaminergic neuronal loss induced by αSyn. These observations were recapitulated with a potent, selective, brain-penetrant USP30 inhibitor, MTX115325, with good drug-like properties. These data strongly support further study of USP30 inhibition as a potential disease-modifying therapy for PD.
Identifiants
pubmed: 37957154
doi: 10.1038/s41467-023-42876-1
pii: 10.1038/s41467-023-42876-1
pmc: PMC10643470
doi:
Substances chimiques
alpha-Synuclein
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
Usp30 protein, mouse
EC 3.1.2.-
Thiolester Hydrolases
EC 3.1.2.-
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
7295Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NINDS NIH HHS
ID : R21 NS109408
Pays : United States
Informations de copyright
© 2023. The Author(s).
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