Background Parkinson's disease (PD) is characterized by α‐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 (G×E) interactions. An inverse association between smoking and the risk of PD is well established, and a previous genome‐wide G×E 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. Objective We sought to determine the mechanism of the smoking–SV2C interaction in a Drosophila model of PD. Methods Flies expressing human α‐synuclein in all neurons develop the hallmarks of PD, including motor dysfunction, loss of dopaminergic (DA) neurons, and formation of α‐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. Results The α‐synuclein–expressing flies treated with nicotine had improved locomotion, DA neuron counts, and α‐synuclein aggregation. However, in α‐synuclein–expressing flies in which SV2L1 and SV2L2 were knocked down, nicotine failed to rescue neurodegeneration. Conclusions This work confirms a G×E interaction between nicotine and SV2, defines a role for this interaction in α‐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 G×E, paving the way for the investigation of additional G×E interactions or the identification of novel G×E. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: Parkinson's disease (PD) is characterized by alpha-synuclein aggregation and loss of dopamine (DA) neurons in the substantia nigra. 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 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. Objective: We sought to determine the mechanism of the smoking-SV2C interaction in a Drosophila model of PD. Methods: Flies expressing human alpha-synuclein in all neurons develop the hallmarks of PD, including motor dysfunction, loss of 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 SV2 knockdown. Results: alpha-synuclein-expressing flies treated with nicotine had improvement in locomotion, DA neuron counts, and in alpha-synuclein aggregation. However, in alpha-synuclein-expressing flies in which Drosophila orthologs of SV2 were knocked down, nicotine failed to rescue neurodegeneration. Conclusions: This 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. Further, this provides proof of concept that our model can be used for mechanistic study of GxE, paving the way for investigation of additional GxE interactions or identification of novel GxE.