Therapeutic targeting of synaptic vesicle glycoprotein 2C (SV2C) in Parkinson's d

There is no cure for Parkinson's disease, and no disease-modifying therapeutic interventions, which halt or slow the progression of the disease, currently exist. While symptomatic interventions exist for Parkinson's disease, many come with debilitating side effects (e.g., dopamine receptor agonists), require invasive procedures (e.g., deep brain stimulation), or wear off after a certain amount of time (e.g., L-DOPA). Thus, new approaches to treat Parkinson's disease are desperately needed. This proposal will investigate whether a novel protein, synaptic vesicle glycoprotein 2C (SV2C), is a viable drug target for treatment of Parkinson's disease. Parkinson's disease is characterized by a loss of dopamine transmission leading to the development of motor deficits. Furthermore, dysregulation of dopamine packaging appears to contribute to the development of Parkinson's disease. SV2C is involved in dopamine regulation, enhancing its sequestration within synaptic vesicles, and its expression is restricted to the areas of the brain affected in Parkinson's disease. Additionally, SV2C has been identified by genome-wide association studies as a risk factor for developing Parkinson's disease, and as a modifier of Parkinson's disease risk and as a modifier of Parkinson's disease patient response to symptomatic (L-DOPA) relief. There is precedent for therapeutically targeting SV2 proteins as the drug Levetiracetam has exhibited efficacy in the treatment of epilepsy and targets synaptic vesicle glycoprotein 2A (SV2A). Due to its role in regulating vesicular dopamine dynamics, a drug targeting SV2C may provide the dual benefit of: improving motor symptoms by regulating vesicular dopamine dynamics, either alone or by improving L-DOPA efficacy, and conferring neuroprotection by minimizing the neurotoxic cytosolic pool of dopamine. Thus, we hypothesized that SV2C mediates dopamine neurodegeneration in Parkinson's disease models and is therefore a viable therapeutic target that may modify disease progression and improve efficacy of symptomatic interventions.