Parkinsonism mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1.
Journal
NPJ Parkinson's disease
ISSN: 2373-8057
Titre abrégé: NPJ Parkinsons Dis
Pays: United States
ID NLM: 101675390
Informations de publication
Date de publication:
04 Feb 2023
04 Feb 2023
Historique:
received:
14
07
2022
accepted:
16
01
2023
pubmed:
5
2
2023
medline:
5
2
2023
entrez:
4
2
2023
Statut:
epublish
Résumé
Recent evidence links dysfunctional lipid metabolism to the pathogenesis of Parkinson's disease, but the mechanisms are not resolved. Here, we generated a new Drosophila knock-in model of DNAJC6/Auxilin and find that the pathogenic mutation causes synaptic dysfunction, neurological defects and neurodegeneration, as well as specific lipid metabolism alterations. In these mutants, membrane lipids containing long-chain polyunsaturated fatty acids, including phosphatidylinositol lipid species that are key for synaptic vesicle recycling and organelle function, are reduced. Overexpression of another protein mutated in Parkinson's disease, Synaptojanin-1, known to bind and metabolize specific phosphoinositides, rescues the DNAJC6/Auxilin lipid alterations, the neuronal function defects and neurodegeneration. Our work reveals a functional relation between two proteins mutated in Parkinsonism and implicates deregulated phosphoinositide metabolism in the maintenance of neuronal integrity and neuronal survival.
Identifiants
pubmed: 36739293
doi: 10.1038/s41531-023-00459-3
pii: 10.1038/s41531-023-00459-3
pmc: PMC9899244
doi:
Types de publication
Journal Article
Langues
eng
Pagination
19Subventions
Organisme : Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)
ID : G0B8119N
Organisme : Fonds Wetenschappelijk Onderzoek (Research Foundation Flanders)
ID : 11E2221N
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 646671
Informations de copyright
© 2023. The Author(s).
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