Synaptic vesicle glycoprotein 2C enhances vesicular storage of dopamine and counters dopaminergic toxicity.
Document Type
Article
Publication Date
5-1-2024
Original Citation
Bucher M,
Dunn A,
Bradner J,
Egerton K,
Burkett J,
Johnson M,
Miller G.
Synaptic vesicle glycoprotein 2C enhances vesicular storage of dopamine and counters dopaminergic toxicity. Eur J Neurosci. 2024;59(10):2483-501.
Keywords
JMG, Animals, Dopamine, Synaptic Vesicles, Membrane Glycoproteins, Mice, Dopaminergic Neurons, Nerve Tissue Proteins, Mice, Inbred C57BL, Humans, Corpus Striatum, Male
JAX Source
Eur J Neurosci. 2024;59(10):2483-501.
ISSN
1460-9568
PMID
38532289
DOI
https://doi.org/10.1111/ejn.16311
Grant
National Institute of Neurological Disorders and Stroke F31NS089242 (ARD
Abstract
Dopaminergic neurons of the substantia nigra exist in a persistent state of vul- nerability resulting from high baseline oxidative stress, high-energy demand, and broad unmyelinated axonal arborisations. Impairments in the storage of dopamine compound this stress because of cytosolic reactions that transform the vital neurotransmitter into an endogenous neurotoxicant, and this toxicity is thought to contribute to the dopamine neuron degeneration that occurs Par- kinson’s disease. We have previously identified synaptic vesicle glycoprotein 2C (SV2C) as a modifier of vesicular dopamine function, demonstrating that genetic ablation of SV2C in mice results in decreased dopamine content and evoked dopamine release in the striatum. Here, we adapted a previously pub- lished in vitro assay utilising false fluorescent neurotransmitter 206 (FFN206) to visualise how SV2C regulates vesicular dopamine dynamics and determined that SV2C promotes the uptake and retention of FFN206 within vesicles. In addition, we present data indicating that SV2C enhances the retention of dopa- mine in the vesicular compartment with radiolabelled dopamine in vesicles isolated from immortalised cells and from mouse brain. Further, we demon- strate that SV2C enhances the ability of vesicles to store the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) and that genetic ablation of SV2C results in enhanced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- induced vulnerability in mice. Together, these findings suggest that SV2C functions to enhance vesicular storage of dopamine and neurotoxicants and helps maintain the integrity of dopaminergic neurons.