Role of urate in protecting mitochondrial function in the brain

描述（由申请人提供）：与所有其他哺乳动物相比，人类和猿的尿酸氧化酶（UOx）基因的多个失活突变导致我们的尿酸盐水平显著升高，并且已经假设通过尿酸盐的有效抗氧化特性赋予选择性优势。然而，在人类中，高尿酸盐水平对健康的唯一既定影响是由于关节（痛风）和肾脏（结石）中的晶体形成而引起的病理性影响。最近，尿酸盐已被确定为帕金森病（PD）风险降低和进展缓慢的一个强大的生物标志物，表明尿酸盐可能具有神经保护作用，并促进临床开发尿酸盐升高作为一种有前途的神经保护策略在PD。线粒体DNA（mtDNA）的氧化损伤和体细胞mtDNA突变随着年龄的增长在黑质神经元中积累，并可能导致衰老和神经退行性疾病（如PD）中的线粒体功能障碍。通过将一个研究CNS线粒体功能障碍的实验室的互补专业知识与另一个表征嘌呤（如尿酸盐）神经保护潜力的实验室相结合，拟议的探索性项目将测试尿酸盐在维持线粒体完整性方面发挥关键作用的中心假设。具体 目的1将评估UOx基因的破坏（其升高尿酸盐水平）是否会减少表达校正缺陷型mtDNA聚合酶γ（PolgD257A）的Polg“mutator”小鼠脑中体细胞mtDNA突变的积累，并减弱这些小鼠的特征性过早衰老表型（包括代谢和行为缺陷）。相反，特异性目的2将决定UOx基因的过表达，这降低了尿酸盐水平，将增强体细胞mtDNA突变的积累，进而加剧早衰表型。从拟议的合作项目中获得的见解将揭示衰老大脑中线粒体功能障碍的一个几乎未被探索但基本的方面，对我们理解线粒体功能的基本神经生物学以及体细胞mtDNA突变的潜在作用具有潜在的高度影响。这项工作也与翻译神经科学以及人类进化有很高的相关性。这可能为探索靶向作用和治疗潜力奠定基础 尿酸盐在PD和其他神经退行性疾病的线粒体缺陷中的作用。

DESCRIPTION (provided by applicant): Multiple inactivating mutations of the urate oxidase (UOx) gene of humans and apes account for our markedly elevated urate levels compared to all other mammals, and have been hypothesized to confer a selective advantage through urate's potent antioxidant properties. However, in humans the only established effects of high urate levels on health are pathological due to crystal formation in joints (gout) and kidney (stones). Recently, urate has been identified as a robust biomarker of reduced risk and slower progression in Parkinson's disease (PD), suggesting that urate may be neuroprotective and prompting clinical development of urate elevation as a promising neuroprotective strategy in PD. Oxidative damage to mitochondrial DNA (mtDNA) and somatic mtDNA mutations accumulate with age in substantia nigra neurons and may contribute to mitochondrial dysfunction in aging and in neurodegenerative disease like PD. By combining the complementary expertise of a laboratory investigating mitochondrial dysfunction in the CNS with another lab characterizing the neuroprotective potential of purines like urate, the proposed exploratory project will test the central hypothesis that urate plays a crucial role in maintaining mitochondrial integrity. Specific Aim 1 will assess whether disruption of the UOx gene, which elevates urate levels, will reduce the accumulation of somatic mtDNA mutations in the brain in Polg "mutator" mice expressing a proofreading-deficient mtDNA polymerase gamma (PolgD257A) and will attenuate the characteristic premature aging phenotype (including metabolic and behavioral deficits) of these mice. Conversely, Specific Aim 2 will determine with overexpression of the UOx gene, which lowers urate levels, will enhance the accumulation of somatic mtDNA mutations and in turn exacerbate the premature aging phenotype. The insights gained from the proposed collaborative project will shed light on a virtually unexplored but fundamental aspect of mitochondrial dysfunction in the aging brain, with a potentially high impact on our understanding of basic neurobiology of mitochondrial function, and the potential role of somatic mtDNA mutations. This work also has high relevance to translational neuroscience as well as human evolution. It may form the foundation for exploring the role and therapeutic potential of targeting urate in mitochondrial deficits of PD and other neurodegenerative diseases.