Vesicular modulation of dopamine neuron toxicity

Abstract The Miller laboratory has been conducting research on the divergent nature of dopamine in neurons for over two decades. Dopamine is an essential neurotransmitter/neuromodulator, but at the same time it represents a potential source of endogenous toxicity. Data from our laboratory and others have clearly demonstrated that improperly stored dopamine, via altered function of the vesicular monoamine transporter (VMAT2) can induce progressive nigrostriatal dopamine neurodegeneration that is strikingly similar to idiopathic Parkinson’s disease. The synthesis, packaging, and degradation of dopamine (i.e. homeostasis) is thus tightly regulated to minimize the potential for toxicity. In the previous funding period, the laboratory provided the first evidence that the synaptic vesicle glycoprotein 2C (SV2C) was a key modulator of vesicular dopamine homeostasis. We demonstrated that SV2C regulates synaptic dopamine release and its expression is altered in human Parkinson’s disease brain tissue. In April, 2020 another laboratory identified SV2C in a large Parkinson’s disease GWAS firmly positioning the protein as a key player in Parkinson’s disease pathogenesis. New preliminary data from our laboratory indicate that SV2C can confer resistance to MPTP and that it prevents leakage of dopamine from the vesicle. These data serve as the basis of our hypothesis that SV2C, through its ability to retain dopamine within synaptic vesicles, confers resistance to dopamine neurotoxicity. We will test this hypothesis through the following specific aims: Aim 1, to examine the mechanisms by which SV2C regulates vesicular dopamine homeostasis and mediates toxicant-induced neurotoxicity. Aim 2, to determine whether introducing the evolutionarily advanced SV2 proteins into the model organism C. elegans can confer protection against dopaminergic toxicity. Aim 3, to determine the functional properties of SV2C in mice. Aim 4, to determine the role of SV2C in PD-related pathogenesis (synuclein-based and toxicant-induced) in mice. Completion of the above specific aims will provide critical information on the role of SV2C in dopamine neuron function, vulnerability to chemicals suspected in the development of Parkinson’s disease, and its potential as a target of therapeutic intervention.