Role of urate in protecting mitochondrial function in the brain

描述(由申请人提供)：人类和类人猿的尿酸氧化酶(UOx)基因的多个失活突变导致我们的尿酸水平显著高于所有其他哺乳动物，并被假设通过尿酸盐的强大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唯一确定的影响是由于关节(痛风)和肾脏(结石)的晶体形成而产生的病理性影响。最近，尿酸盐被认为是帕金森病(PD)风险降低和进展缓慢的强有力的生物标志物，提示尿酸盐可能具有神经保护作用，并促使临床将尿酸升高作为PD的一种有前途的神经保护策略。线粒体DNA氧化损伤(MtDNA)和体细胞mtDNA突变随着年龄的增长在黑质神经元中积累，并可能在衰老和帕金森病等神经退行性疾病中导致线粒体功能障碍。通过结合一个研究中枢神经系统线粒体功能障碍的实验室和另一个表征尿酸盐等嘌呤神经保护潜力的实验室的互补专业知识，拟议的探索性项目将检验尿酸盐在维持线粒体完整性方面发挥关键作用的核心假设。特定的 目的1将评估UOx基因的破坏是否会减少表达校对缺陷mtDNA聚合酶伽马(PolgD257A)的Polg“Mutator”小鼠的体细胞mtDNA突变在脑中的积累，并将减轻这些小鼠特有的过早衰老表型(包括代谢和行为缺陷)。相反，特定的目标2将决定UOx基因的过度表达，这将降低尿酸水平，增加体细胞mtDNA突变的积累，并反过来加剧过早衰老的表型。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，这可能对我们理解线粒体功能的基本神经生物学以及体细胞mtDNA突变的潜在作用产生很大影响。这项工作对翻译神经科学和人类进化也有很高的相关性。这可能为探索靶向的作用和治疗潜力奠定基础。 尿酸在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.