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Abnormal accumulation of lipid droplets in neurons induces the conversion of alpha-Synuclein to proteolytic resistant forms in a Drosophila model of Parkinson's disease.
PLoS Genet, 17(11):e1009921.
Parkinson's disease (PD) is a neurodegenerative disorder characterized byalpha-synuclein (αSyn) aggregation and associated with abnormalities in lipidmetabolism. The accumulation of lipids in cytoplasmic organelles called lipiddroplets (LDs) was observed in cellular models of PD. To investigate thepathophysiological consequences of interactions between αSyn and proteins thatregulate the homeostasis of LDs, we used a transgenic Drosophila model of PD, inwhich human αSyn is specifically expressed in photoreceptor neurons. We first foundthat overexpression of the LD-coating proteins Perilipin 1 or 2 (dPlin1/2), whichlimit the access of lipases to LDs, markedly increased triacylglyclerol (TG) loadedLDs in neurons. However, dPlin-induced-LDs in neurons are independent of lipidanabolic (diacylglycerol acyltransferase 1/midway, fatty acid transportprotein/dFatp) and catabolic (brummer TG lipase) enzymes, indicating thatalternative mechanisms regulate neuronal LD homeostasis. Interestingly, theaccumulation of LDs induced by various LD proteins (dPlin1, dPlin2, CG7900 orKlarsichtLD-BD) was synergistically amplified by the co-expression of αSyn, whichlocalized to LDs in both Drosophila photoreceptor neurons and in human neuroblastomacells. Finally, the accumulation of LDs increased the resistance of αSyn toproteolytic digestion, a characteristic of αSyn aggregation in human neurons. Wepropose that αSyn cooperates with LD proteins to inhibit lipolysis and that bindingof αSyn to LDs contributes to the pathogenic misfolding and aggregation of αSyn inneurons.
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