Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 11, Pages E2253-E2262Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1616892114
Keywords
Parkinson disease; SV2C; synaptic vesicles; dopamine; alpha-synuclein
Categories
Funding
- National Institute of Environmental Health Services (NIEHS) [R01ES023839, P30ES019776]
- Lewis Dickey Memorial Fund
- National Institute of Neurological Disorders and Stroke (NINDS) [F31NS089242]
- NIEHS [K99ES024570]
- Neuropathology Core of the Emory Neuroscience NINDS Core Facilities
- NIH Grant [P30NS055077, P50AB005136]
- Udall Parkinson's Disease Center at Emory University
- NINDS Grant [P50NS071669]
- University of Washington Aging and Disability Resource Center Brain Bank
- National Institute on Aging Intramural Research Program Grant [NIA AG000928, AG000929]
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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 alpha-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 alpha-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.
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