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

 描述（由申请人提供）：帕金森病影响1%的60岁以上的成年人，是第二常见的神经退行性疾病。其特征在于黑质背侧部的多巴胺能神经元的进行性损失，并且临床上，其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、胃肠道中断和睡眠障碍。目前没有预防疾病发作或遏制疾病进展的治疗方法，确定药物干预的潜在新靶点对于降低疾病发病率和严重程度至关重要。PD治疗的一个有前途的目标是多巴胺能囊泡。我们的实验室和其他实验室已经充分证实，受损的囊泡功能和多巴胺的能力-例如，由于囊泡单胺转运蛋白2（VMAT 2）的表达不足-可以导致进行性多巴胺能变性和增强对多巴胺能毒物的脆弱性。[相反，增强的囊泡功能具有神经保护作用]。因此，我们的实验室有兴趣表征多巴胺囊泡功能的新靶点，如突触囊泡糖蛋白2C（SV 2C）。SV 2C基因型介导尼古丁使用的保护能力，这是PD风险最强的环境介质。针对SV 2C可能使我们能够利用尼古丁的治疗潜力，而不会使患者遭受与尼古丁使用相关的负面健康后果。我们已经开发了SV 2C-KO小鼠，这将使我们能够确定这种蛋白质在介导多巴胺处理和释放及其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，SV 2C介导多巴胺囊泡包装和释放，提供了进一步的证据，在PD中靶向SV 2C的潜在治疗价值。该项目的目标是证明SV 2C确实介导多巴胺的处理和释放，MPTP对多巴胺能毒性的脆弱性和尼古丁的神经保护作用。这项研究的结果将显示SV 2C在预防病理性多巴胺能变性方面的作用，并将评估其作为PD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.