Abstract Details

Title SV2C is required for nicotine-mediated rescue of alpha-synuclein neurotoxicity

Topic Movement Disorders

Presentation(s) S27 - Movement Disorders: Basic Science (2:24 PM-2:32 PM)

Poster/Presentation
Number 003

Objective

To develop a Drosophila model for testing gene-environment interactions in Parkinson’s disease.

Background Parkinson’s disease (PD) is a neurodegenerative disease characterized by α-synuclein aggregation and the progressive 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 with one another, termed gene-environment (GxE) interactions. An inverse association between smoking cigarettes and risk of developing 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. We sought to determine the mechanism of the smoking-SV2C interaction in a Drosophila model of PD.

Design/Methods In this model, human α-synuclein is expressed in all neurons, and flies 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 We demonstrate that α-synuclein-expressing flies treated with nicotine (the presumed active ingredient in tobacco) have significant improvement in locomotion, in total number of brain cells and in DA neuron counts, in a dose-dependent manner. However, in α-synuclein-expressing flies in which Drosophila homologs of SV2C are knocked down, nicotine fails to rescue neurodegeneration and in fact further worsens motor behavior.

Conclusions This work provides proof of concept that our model can be used for mechanistic study of GxE, paving the way for investigation of additional known GxE interactions or identification of novel GxE.

Authors/Disclosures
Sabrina Clemens (Brigham & Women's Hospital) PRESENTER	Sabrina Clemens has received research support from NINDS.
Abby L. Olsen, MD (University of Pittsburgh)	An immediate family member of Dr. Olsen has received personal compensation for serving as an employee of Rheos Medicines. An immediate family member of Dr. Olsen has received personal compensation for serving as an employee of Novasenta. An immediate family member of Dr. Olsen has received personal compensation for serving as an employee of Biohaven. The institution of Dr. Olsen has received research support from NINDS. The institution of Dr. Olsen has received research support from DoD. The institution of Dr. Olsen has received research support from American Parkinson's Disease Association. The institution of Dr. Olsen has received research support from Alzheimer's Association.

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