Abstract
Parkinson’s disease is a neurodegenerative disorder characterized by accumulation of alpha-synuclein (αSyn) aggregates and by abnormalities in lipid storage. To investigate the potential pathophysiological consequences of interactions between αSyn and proteins that regulate the homeostasis of intracellular lipid droplets (LDs), we employed a transgenic Drosophila model of PD in which human αSyn is specifically expressed in photoreceptor neurons. We found that overexpression of the LD-coating proteins perilipin 1 and 2 (dPlin1/2) markedly increased LD accumulation in the neurons. Perilipins also co-localized with αSyn at the LD surface in both Drosophila photoreceptor neurons (dPlin2) and human neuroblastoma cells (PLIN3). Co-expression of αSyn and dPlin2 in photoreceptor neurons synergistically amplified LD content through a mechanism involving LD stabilization, independently of Brummer-mediated lipolysis or de novo synthesis of triacylglycerols. Accumulation of LDs also increased the resistance of αSyn to proteolytic digestion, a phenomenon associated with αSyn aggregation in human neurons. Our results suggest that binding of αSyn to PLIN-coated LDs stabilizes the LD structure and may contribute to the pathogenic misfolding and aggregation of αSyn in neurons.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
The previous version of the manuscript uploaded was missing the supplemental figures. There was also an error in the list of authors (Bertrand Mollereau should be last author and Victor Girard first author).