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.

Victor Girard,Andrej Shevchenko,Nathalie Davoust,Bertrand Mollereau,Thierry Baron,Oskar Knittelfelder,Jean-Noel Arsac,Marion Celle,Daan M Van Den Brink,Ronald P Kühnlein,Florence Jollivet,Gilles Chatelain

doi:10.1371/journal.pgen.1009921

Abstract

Parkinson's disease (PD) is a neurodegenerative disorder characterized by alpha-synuclein (αSyn) 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 αSyn and proteins that regulate the homeostasis of LDs, we used a transgenic Drosophila model of PD, in which human αSyn 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 (brummer TG lipase) enzymes, indicating that alternative mechanisms regulate neuronal LD homeostasis. Interestingly, the accumulation of LDs induced by various LD proteins (dPlin1, dPlin2, CG7900 or KlarsichtLD-BD) was synergistically amplified by the co-expression of αSyn, which localized to LDs in both Drosophila photoreceptor neurons and in human neuroblastoma cells. Finally, the accumulation of LDs increased the resistance of αSyn to proteolytic digestion, a characteristic of αSyn aggregation in human neurons. We propose that αSyn cooperates with LD proteins to inhibit lipolysis and that binding of αSyn to LDs contributes to the pathogenic misfolding and aggregation of αSyn in neurons.

Highlights

Lipids play crucial roles in many essential cellular functions, including membrane formation, energy production, intracellular and intercellular signal transduction, and regulation of cell death
Parkinson’s disease (PD) is a neurodegenerative disease characterized by the neurotoxic aggregation of the alpha-synuclein protein
Using human neuronal cell lines and the fly, we could show that lipid droplets (LDs)-coating and αSyn proteins localize at the surface of LDs

Summary

Introduction

Lipids play crucial roles in many essential cellular functions, including membrane formation, energy production, intracellular and intercellular signal transduction, and regulation of cell death. Fatty acids (FAs) taken up into or synthesized within cells are stored in discrete organelles known as lipid droplets (LDs), which consist of a core of neutral lipids predominantly triacylglycerols (TGs) and sterol esters, surrounded by a monolayer of phospholipids containing numerous LD proteins [1]. The mechanisms by which fat is stored and remobilized in LDs are dependent on evolutionarily conserved canonical anabolic and catabolic enzymes [6]. LD biogenesis is initiated at the endoplasmic reticulum membrane, where lipogenesis enzymes, such as Drosophila diacylglycerol acyltransferase 1 (DGAT1), encoded by the midway (mdy) gene, catalyze the rate limiting step of TG synthesis [7,8]. Fatty acid transport protein 1 (dFatp in Drosophila), which functions in a complex with diacylglycerol acyltransferase 2 (DGAT2), promotes LD expansion in C. elegans, Drosophila and mammalian cells [9,10,11]. Lipolysis is catalysed by lipases, such as the central and evolutionarily conserved TG lipase Brummer in the fly (Bmm called dATGL), ortholog of mammalian adipose triglyceride lipase (ATGL) [14]

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Conclusion