Nicotine-Mediated Rescue of α-Synuclein Toxicity Requires Synaptic Vesicle Glycoprotein 2 in Drosophila

BackgroundParkinson's disease (PD) is characterized by alpha-synuclein aggregation and loss of dopamine neurons. Risk of PD arises due to a combination of genetic and environmental factors, which may interact, termed gene-environment (GxE) interactions. An inverse association between smoking and the risk of PD is well established, and a previous genome-wide GxE interaction study identified genetic variation in the synaptic-vesicle glycoprotein 2C (SV2C) locus as an important mediator of the degree to which smoking is inversely associated with PD. ObjectiveWe sought to determine the mechanism of the smoking-SV2C interaction in a Drosophila model of PD. MethodsFlies expressing human alpha-synuclein in all neurons develop the hallmarks of PD, including motor dysfunction, loss of dopaminergic (DA) neurons, and formation of alpha-synuclein inclusions. We assessed the effects of increasing doses of nicotine on these parameters of neurodegeneration, in the presence or absence of knockdown of two Drosophila orthologues of SV2, hereafter referred to as SV2L1 and SV2L2. ResultsThe alpha-synuclein-expressing flies treated with nicotine had improved locomotion, DA neuron counts, and alpha-synuclein aggregation. However, in alpha-synuclein-expressing flies in which SV2L1 and SV2L2 were knocked down, nicotine failed to rescue neurodegeneration. ConclusionsThis work confirms a GxE interaction between nicotine and SV2, defines a role for this interaction in alpha-synuclein proteostasis, and suggests that future clinical trials on nicotine should consider genetic variation in SV2C. Furthermore, this provides proof of concept that our model can be used for the mechanistic study of GxE, paving the way for the investigation of additional GxE interactions or the identification of novel GxE. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Automated summary

This study investigated the mechanism of smoking-SV2C interaction in a Drosophila model of PD, confirming a GxE interaction between nicotine and SV2, and suggesting the consideration of genetic variation in SV2C in future clinical trials on nicotine.