Jacquemyn, J., Kuenen, S., Swerts, J., Pavie, B., Vijayan, V., Kilic, A., Chabot, D., Wang, Y.C., Schoovaerts, N., Corthout, N., Verstreken, P. (2023). Parkinsonism mutations in DNAJC6 cause lipid defects and neurodegeneration that are rescued by Synj1.  NPJ Parkinsons Dis. 9(1): 19.

FBrf0255671

Research paper

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.

PMC9899244 (PMC) (EuropePMC)