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, though SV2C with its restricted basal ganglia distribution has no known function. SV2C is emerging as a potentially relevant protein in Parkinsons disease (PD), as it is a genetic modifier of nicotine neuroprotection and sensitivity to L-DOPA. 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. Further, SV2C expression is dramatically altered in postmortem brain tissue from PD cases, but not in Alzheimers disease, progressive supranuclear palsy or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated -synuclein. These data establish SV2C as a novel mediator of dopamine neuron function and suggest that SV2C disruption is a unique feature of PD that likely contributes to dopaminergic dysfunction.