SV2C as a novel mediator of transmitter release and neuroprotection in dopamine cells

 描述(申请人提供)：帕金森氏症影响1%的60岁以上的成年人，是第二常见的神经退行性疾病。它的特征是黑质致密部多巴胺能神经元的进行性丢失，临床上表现为严重的运动障碍，包括运动缓慢、运动迟缓、静止性震颤、胃肠道紊乱和睡眠障碍。目前还没有预防疾病发生或遏制疾病发展的治疗方法，为药物干预确定潜在的新目标将是降低疾病发生率和严重程度的当务之急。帕金森病治疗的一个有希望的靶点是多巴胺能囊泡。我们的实验室和其他实验室已经很好地证实，囊泡功能和多巴胺的容量受损-例如，由于囊泡单胺转运体2(VMAT2)表达不足-可以导致进行性的多巴胺能退化和对多巴胺能毒物的易感性增加。[相反，增强的囊泡功能具有神经保护作用]。因此，我们的实验室对表征多巴胺囊泡功能的新靶点很感兴趣，例如突触囊泡糖蛋白2C(SV2C)。SV2C基因介导尼古丁使用的保护力，尼古丁是帕金森病风险的最强环境介体。靶向SV2C可能允许我们利用尼古丁的治疗潜力，而不会使患者暴露于与尼古丁使用相关的负面健康后果。我们已经开发了SV2C-KO小鼠，这将使我们能够确定该蛋白在介导多巴胺处理和释放以及它与尼古丁的功能相互作用中的作用。初步的电化学数据表明，SV2C介导了多巴胺的囊泡包装和释放，为靶向SV2C在PD中的潜在治疗价值提供了进一步的证据。本项目的目的是证明SV2C确实介导多巴胺的处理和释放、MPTP对多巴胺能毒性的易感性以及尼古丁的神经保护作用。这项研究的结果将显示SV2C在多大程度上对病理性多巴胺能变性起到保护作用，并将评估其作为帕金森病治疗靶点的潜力。

 DESCRIPTION (provided by applicant): Parkinson's disease affects 1% of adults over the age of 60 and is the second-most common neurodegenerative disease. It is characterized by progressive loss of the dopaminergic neurons of the substantia nigra pars compacta, and clinically, it manifests with severe motor impairments including slowness of movement, bradykinesia, resting tremor, gastrointestinal disruptions, and sleep disturbances. There are currently no treatments to prevent disease onset or curtail disease progression, and identifying potential new targets for pharmaceutical interventions will be imperative to reduce disease incidence and severity. A promising target for PD therapeutics is the dopaminergic vesicle. It has been well-established by our lab and others that impaired vesicular function and capacity for dopamine-for example, as a result of under- expression of the vesicular monoamine transporter 2 (VMAT2)-can lead to progressive dopaminergic degeneration and enhanced vulnerability to dopaminergic toxicants. [Conversely, enhanced vesicular function is neuroprotective]. Our lab is therefore interested in characterizing novel targets of dopamine vesicle function, such as the synaptic vesicle glycoprotein 2C (SV2C). SV2C genotype mediates the protective power of nicotine use, which is the strongest environmental mediator of PD risk. Targeting SV2C may allow us to harness the therapeutic potential of nicotine without exposing patients to negative health consequences associated with nicotine use. We have developed SV2C-KO mice that will allow us to determine this protein's role in mediating dopamine handling and release and its functional interaction with nicotine. Preliminary electrochemistry data suggest that SV2C mediates dopamine vesicular packaging and release, providing further evidence of a potential therapeutic value for targeting SV2C in PD. The goal of this project is to demonstrate that SV2C indeed mediates dopamine handling and release, vulnerability to dopaminergic toxicity by MPTP and neuroprotection by nicotine. Results from this study will show to what extent SV2C plays a role in protecting against pathological dopaminergic degeneration, and it will evaluate its potential as a therapeutic target for PD.