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. 2021 Nov 17;17(11):e1009921. doi: 10.1371/journal.pgen.1009921. eCollection 2021 Nov.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified / genetics
  • Disease Models, Animal
  • Drosophila Proteins / genetics
  • Drosophila melanogaster / genetics
  • Humans
  • Lipid Droplets / metabolism
  • Lipid Metabolism / genetics*
  • Lipolysis / genetics
  • Membrane Transport Proteins / genetics
  • Neuroblastoma / genetics
  • Neurons / metabolism*
  • Neurons / pathology
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Perilipin-2 / genetics
  • Protein Aggregation, Pathological / genetics
  • Protein Aggregation, Pathological / pathology
  • Proteolysis
  • alpha-Synuclein / genetics*


  • Drosophila Proteins
  • Membrane Transport Proteins
  • Perilipin-2
  • alpha-Synuclein
  • klar protein, Drosophila

Grant support

This work was supported by a grant from the Association France Parkinson to BM. VG salary was supported by the Fondation pour la Recherche Médicale (grant FDT201904008373), ENS Fond Recherche, Servier Research Institute, and the Laboratory of Modelling and Biology of the Cell. AS was supported by Deutsche Forschungsgemeinschaft (grant FOR 2682). RKP was supported by Universität Graz. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.