Uric Acid:novel therapeutic target for Parkinson's Disease

描述（由申请人提供）：人体尿酸是一种强抗氧化剂，也是嘌呤代谢的最终产物。低血尿酸现在成为特发性帕金森病（PD）的主要分子危险因素。此外，在两项大型前瞻性临床研究中，我们的初步研究结果表明，基于临床和神经影像学测量，早期PD患者的血浆和脑脊液尿酸水平是PD进展速度较慢的高度显著预测因子。这些观察结果支持尿酸或其决定因素在帕金森病中的一种新的神经保护作用，并促使我们探索它们在帕金森病动物模型中的作用。本研究的核心假设是，尿酸及其决定因素对帕金森病动物模型中的多巴胺能神经元退化具有保护作用。我们将研究尿酸及其前体肌苷在PD小鼠MPTP模型中的神经保护作用，采用互补的遗传和药理学方法（全身或局部，急性或慢性）升高尿酸。这项工作将定义环境神经毒物和新确定的候选神经保护剂之间的典型相互作用，这可能特别适合治疗干预。提出的实验将为为什么尿酸可以预测降低风险和减缓疾病进展建立一个生物学基础。该项目的机制见解可能会为预防和减缓PD提供新颖而现实的药理学策略。

DESCRIPTION (provided by applicant): In humans uric acid constitutes a strong antioxidant as well as the end product of purine metabolism. Lower blood uric acid is now emerging as a major molecular risk factor for idiopathic Parkinson's disease (PD). Moreover, our preliminary findings have demonstrated that plasma and CSF uric acid levels in early PD are highly significant predictors of a slower rate of PD progression based on clinical and neuroimaging measures in two large prospective clinical studies. These observations support a novel neuroprotective effect of uric acid or its determinants in PD, and prompted us to explore their role in an animal model of PD. The core hypothesis pursued by this proposal is that uric acid and its determinants confer protection against dopaminergic neuron degeneration in an animal model of PD. We will investigate the neuroprotective effects of uric acid and its precursor inosine in the mouse MPTP model of PD, using complementary genetic and pharmacological approaches to elevating uric acid (systemically or locally; acutely or chronically). The proposed work will define a prototypical interaction between an environmental neurotoxicant and a newly identified candidate neuroprotectant, which may be particularly amenable to therapeutic interventions. The proposed experiments stand to establish a biological basis for why uric acid predicts reduced risk and slower progression of the disease. Mechanistic insights from the project may substantiate novel yet realistic pharmacological strategies for preventing and slowing PD. PUBLIC HEALTH RELEVANCE The proposed research stands to elucidate neuroprotective effects of uric acid and its precursor inosine in a prototypic toxicant model of PD. The results of these studies may thus establish a biological basis for the inverse epidemiological and clinical associations between uric acid and PD, and provide a foundation for future mechanistic investigations. Together, the specific aims of this proposal seek to provide conceptually important and clinically relevant insights into the pathophysiology, the epidemiology and potentially the treatment of PD and related neurological disorders.