Parkinson mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1
Jacquemyn, J.; Kuenen, S.; Swerts, J.; Pavie, B.; Vijayan, V.; Kilic, A.; Chabot, D.; Wang, Y.-C.; Schoovaerts, N.; Verstreken, P.
Show abstract
Recent evidence links dysfunctional lipid metabolism to the pathogenesis of Parkinsons disease, but the mechanisms are not resolved. Here, we created 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 Parkinsons disease, Synaptojanin-1, known to bind and synthesize specific phosphoinositides, strongly rescues the DNAJC6/Auxilin neuronal defects and neurodegeneration. Our work reveals a functional relation between two proteins mutated in Parkinsons disease and implicates deregulated phosphoinositide metabolism in the maintenance of neuronal integrity and neuronal survival in Parkinsonism.
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