Alpha-synuclein enhances lipid droplet accumulation in neurons in a Drosophila model of Parkinson's disease

Mollereau, B.; Girard, V.; Jollivet, F.; Knittelfelder, O.; Arsac, J.-N.; Chatelain, G.; Van den Brink, D.; Baron, T.; Shevchenko, A.; Davoust-Nataf, N.

doi:10.1101/2020.09.16.299354

bioRxiv · 10.1101/2020.09.16.299354

Alpha-synuclein enhances lipid droplet accumulation in neurons in a Drosophila model of Parkinson's disease

Mollereau, B.·Girard, V.·Jollivet, F.·Knittelfelder, O.·Arsac, J.-N.·Chatelain, G.·Van den Brink, D.·Baron, T.·Shevchenko, A.·Davoust-Nataf, N.

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Abstract

Parkinsons disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein (Syn) aggregation and associated with abnormalities in lipid metabolism. The accumulation of lipids in cytoplasmic organelles called lipid droplets (LDs) was observed in cellular models of PD. To investigate the pathophysiological consequences of interactions between Syn and proteins that regulate the homeostasis of LDs, we used a transgenic Drosophila model of PD, in which human Syn is specifically expressed in photoreceptor neurons. We first found that overexpression of the LD-coating proteins perilipin 1 or 2 (dPlin1/2), which limit the access of lipases to LDs, markedly increased triacylglyclerol (TG) loaded LDs in neurons. However, dPlin-induced-LDs in neurons are independent of lipid anabolic (diacylglycerol acyltransferase 1/Midway, fatty acid transport protein/dFatp) and catabolic (lipase Brummer) enzymes, indicating that non-canonical mechanisms regulate neuronal LD homeostasis. Interestingly, the accumulation of LDs induced by several distinct LD proteins (dPlin1, dPlin2, CG7900 or KlarsichtLD-BD) was synergistically amplified by the co-expression of Syn, which was found at the surface of LDs both in photoreceptors neurons of Drosophila and in human neuroblastoma cells. Finally, the accumulation of LDs increased the resistance of Syn to proteolytic digestion, a phenomenon associated with Syn aggregation in human neurons. We thus propose that Syn cooperates with LD proteins to inhibit lipolysis and that binding of Syn to LDs contributes to the pathogenic misfolding and aggregation of Syn in neurons.

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Mollereau, B., Girard, V., Jollivet, F., Knittelfelder, O., Arsac, J.-N., Chatelain, G., Van den Brink, D., Baron, T., Shevchenko, A., Davoust-Nataf, N.. 2020-09-17. Alpha-synuclein enhances lipid droplet accumulation in neurons in a Drosophila model of Parkinson's disease. https://doi.org/10.1101/2020.09.16.299354

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