title: Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease.
abstract: Members of the synaptic vesicle glycoprotein 2 (SV2) family of proteins are involved in synaptic function throughout the brain. The ubiquitously expressed SV2A has been widely implicated in epilepsy, although SV2C with its restricted basal ganglia distribution is poorly characterized. SV2C is emerging as a potentially relevant protein in Parkinson disease (PD), because it is a genetic modifier of sensitivity to l-DOPA and of nicotine neuroprotection in PD. Here we identify SV2C as a mediator of dopamine homeostasis and report that disrupted expression of SV2C within the basal ganglia is a pathological feature of PD. Genetic deletion of SV2C leads to reduced dopamine release in the dorsal striatum as measured by fast-scan cyclic voltammetry, reduced striatal dopamine content, disrupted α-synuclein expression, deficits in motor function, and alterations in neurochemical effects of nicotine. Furthermore, SV2C expression is dramatically altered in postmortem brain tissue from PD cases but not in Alzheimer disease, progressive supranuclear palsy, or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated α-synuclein. These data establish SV2C as a mediator of dopamine neuron function and suggest that SV2C disruption is a unique feature of PD that likely contributes to dopaminergic dysfunction.
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322.
authors.forename: Amy R
authors.identifier: 0000-0001-6437-6099
authors.initials: AR
authors.lastname: Dunn
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Stout
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322.
authors.forename: Minagi
authors.initials: M
authors.lastname: Ozawa
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Lohr
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322.
authors.forename: Carlie A
authors.initials: CA
authors.lastname: Hoffman
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322.
authors.forename: Alison I
authors.initials: AI
authors.lastname: Bernstein
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322.
authors.forename: Minzheng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Transgenics Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Sgobio
authors.affiliation: Transgenics Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Namratha
authors.initials: N
authors.lastname: Sastry
authors.affiliation: Transgenics Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322.
authors.forename: W Michael
authors.initials: WM
authors.lastname: Caudle
authors.affiliation: Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322; gary.miller@emory.edu.|Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, GA 30322.|Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322.|Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Gary W
authors.identifier: 0000-0001-8984-1284
authors.initials: GW
authors.lastname: Miller
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism; D015415:Biomarkers; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D008124:Locomotion; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009538:Nicotine / Q000378:metabolism / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011485:Protein Binding; D013572:Synaptic Vesicles / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C585899:SV2C protein, human; D051844:alpha-Synuclein; D009538:Nicotine; D004298:Dopamine
keywords: Parkinson disease; SV2C; dopamine; synaptic vesicles; α-synuclein