RT Journal Article
SR Electronic
T1 Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson’s disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 077586
DO 10.1101/077586
A1 Amy R. Dunn
A1 Kristen A. Stout
A1 Minagi Ozawa
A1 kelly M. Lohr
A1 Alison I. Bernstein
A1 Yingjie Li
A1 Minzheng Wang
A1 Carmelo Sgobio
A1 Namratha Sastry
A1 Huaibin Cai
A1 W. Michael Caudle
A1 Gary W. Miller
YR 2016
UL http://biorxiv.org/content/early/2016/09/26/077586.abstract
AB 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 Parkinson’s disease, 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 Parkinson’s disease (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 Alzheimer’s disease, progressive supranuclear palsy or multiple system atrophy. This disruption was paralleled in mice overexpressing mutated α-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