Parkinson’s disease is caused by a combination of genetic and environmental factors, one curious example being that people who smoke appear to be less likely to develop Parkinson’s. This may be due to interactions between nicotine and genetic variations in synaptic-vesicle glycoprotein 2C (SV2C). Parkinson’s is characterized by aggregation of α-synuclein protein and loss of dopaminergic neurons in the part of the brain known as the substantia nigra. Researchers were able to duplicate Parkinson’s symptoms in Drosophila flies engineered to express human α-synuclein, and found that dosing them with nicotine improved their locomotion and dopamine receptor counts and reduced α-synuclein aggregation. However, this was only true for flies that expressed the fruit fly equivalent of SV2C—other flies showed no improvement. So far, human trials of nicotine as a therapeutic or preventative for Parkinson’s show little success. This study suggests that the benefit of nicotine may apply to those with a specific genetic makeup, which could enable more targeted studies or more focused therapies. In addition, creation of a successful Drosophila model will allow researchers to study the mechanics of gene-environment interactions in Parkinson’s disease in more depth.
Full abstract, to be presented at the American Neurological Association 2022 Annual Meeting, October 22-25, 2022 in Chicago, and published in Annals of Neurology:
Nicotine-mediated Rescue of Alpha-synuclein Toxicity Requires Synaptic Vesicle Glycoprotein 2c
Abby Olsen, University of Pittsburgh
Co-author: Sabrina Clemens, BA
Background: Parkinson’s disease (PD) is characterized by α-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 α-synuclein in all neurons develop the hallmarks of PD, including motor dysfunction, loss of 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 SV2C knockdown. Results: α-synuclein-expressing flies treated with nicotine had improvement in locomotion, DA neuron counts, and in α-synuclein aggregation. However, in α-synuclein-expressing flies in which Drosophila homologs of SV2C are knocked down, nicotine failed to rescue neurodegeneration. Conclusions: This work confirms a GxE interaction between nicotine and SV2C, defines a role for this interaction in α-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.
All abstracts from ANA2022 will be available in Annals of Neurology starting at 3:01 p.m. U.S. Eastern Time on October 14. This research is under embargo until that time. Contact Katherine Pflaumer (kpflaumer@steegethomson.com) for additional highlighted abstracts, full meeting abstracts, and call-in information for the ANA2022 Media Roundtable (Oct. 25, 11 a.m. U.S. Central).
