Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson’s disease

Abstract

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 fastscan 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 Parkinson's disease | synaptic vesicles | dopamine | SV2C

Human α-synuclein overexpression in mouse serotonin neurons triggers a depressive-like phenotype. Rescue by oligonucleotide therapy

“…Synaptic dysfunction and altered axonal transport has been postulated to be some of the earliest pathological events in PD, in which α-Syn is considered a hub protein by interacting with many synaptic proteins, such as monoamine transporters, cytoskeletal components, chaperones, and several SV-associated proteins [52,73,74]. In this regard, increases of the SV2C protein -enriched in the basal ganglia and preferentially localized in DA neurons-were reported in postmortem PD brain tissue and in mice overexpressing mutant α-Syn [59]. Similarly, we found increased levels of SV2A protein-expressed ubiquitously in the brain-and even co-localizing with h-α-Syn in axonal swellings through CPu and Cg of AAV5 mouse model.…”

“…To determine whether the h-α-Syn accumulation in innervation networks can alter the density of synaptic proteins, such as the synaptic vesicle (SV)-associated proteins, which are ubiquitously expressed in the brain and modulate vesicular function [59], we performed an exploratory analysis of the SV2A protein levels in Cg and CPu from mice overexpressing h-α-Syn in raphe 5-HT neurons. Immunofluorescence analysis showed a progressive increase in punctate SV2A staining in these regions compared to vehicletreated mice (p < 0.01; Fig.…”

Synaptic vesicle glycoprotein 2C enhances vesicular storage of dopamine and counters dopaminergic toxicity

“…Although we have not identified a direct proteinprotein interaction between VMAT2 and SV2C, these proteins appear to work in concert to modulate dopamine dynamics (Dunn et al, 2017). A study that performed transcriptomics in mice with knock-out of VMAT2 in norepinephrine neurons identified SV2C as the gene with the highest enrichment in expression following VMAT2 knock-out in multiple brain areas (Isingrini et al, 2023).…”

“…A study that performed transcriptomics in mice with knock-out of VMAT2 in norepinephrine neurons identified SV2C as the gene with the highest enrichment in expression following VMAT2 knock-out in multiple brain areas (Isingrini et al, 2023). We have additionally shown that animals lacking SV2C have decreased dopamine content in the striatum, as well as impaired evoked dopamine release (Dunn et al, 2017). These animals also displayed decreased locomotor activity correlating with the decrease in dopamine transmission (Dunn et al, 2017).…”

“…(GBA)-associated Parkinson's Disease risk, Parkinson's disease patient's response to L-DOPA, and most recently directly as a risk-modifier for Parkinson's disease (Altmann et al, 2016;Foo et al, 2020;Gan-Or et al, 2015;Grover, Kumar-Sreelatha et al, 2021). Additionally, our laboratory has demonstrated aberrant SV2C staining patterns in post-mortem brain tissue from people with Parkinson's disease, and an interaction between SV2C and alpha-synuclein (Dunn et al, 2017).…”