Developing Tools to Understand an Alternative Fate of Urate in Neurodegenerative Diseases

摘要 尿酸盐是尿酸的一种盐形式，主要存在于循环中，被认为是主要的血浆 抗氧化剂。确诊时血清尿酸水平低与疾病进展加速和 降低了几种神经退行性疾病患者的存活率。例如，帕金森氏症患者的尿酸水平较低 疾病(PD)患者，这与纹状体多巴胺转运体丢失和晚期临床相关 运动障碍的进展。同样，几项研究表明，尿酸盐水平可能作为一种 肌萎缩侧索硬化症(ALS)进展的预后生物标志物，但仍不清楚为什么低尿 酸反映了糟糕的存活率。最近，一项旨在提高帕金森病患者尿酸水平(肌苷补充)的巨大努力 患者没有提供临床益处或改善患者结果。为什么主修课的补充部分 在已知存在氧化应激的疾病中，血浆抗氧化剂对患者没有任何好处？ 我们在研究代谢物对蛋白质的化学修饰方面的专业知识促使我们考虑另一种选择 当氧化应激可能压倒尿酸盐抗氧化能力的再生时，尿酸盐的命运。我们 假设低血尿酸反之反映了尿酸酸氧化增加，从而产生活性尿酸根 可以对蛋白质赖氨酸残基进行化学修饰，改变蛋白质的结构或功能，这一过程被称为 蛋白质的尿苷酸化。尿酸盐类抗氧化剂的益处和尿酸盐氧化对自由基的破坏之间的平衡， 可能独特地取决于氧化应激的位置和性质。在这个R03中，我们正在着手 探索性研究，以更好地理解为什么尿酸盐治疗可能没有预期的那么成功。我们的 目标是生成和验证新的工具，这些工具将在未来帮助运动障碍研究人员进行测试 一系列临床前模型和人类生物样本中蛋白质尿苷酸化的相关性。

ABSTRACT Urate is the salt form of uric acid predominantly found in the circulation and is considered a major plasma antioxidant. Low levels of serum urate at diagnosis are associated with accelerated disease progression and lower patient survival in several neurodegenerative diseases. For example, urate levels are lower in Parkinson’s Disease (PD) patients and this correlates with loss of the striatal dopamine transporter and an advanced clinical progression in motor deficits. Similarly, several studies have suggested that urate levels may offer value as a prognostic biomarker for Amyotrophic Lateral Sclerosis (ALS) progression, yet it remains unclear why low uric acid reflects poor survival. Recently, a large effort to increase urate levels (inosine supplementation) in PD patients offered no clinical benefit or improvement in patient outcomes. Why does the supplementation of a major plasma antioxidant confer no benefit to patients in diseases where oxidative stress is known to be present? Our expertise in studying the chemical modification of proteins by metabolites led us to consider an alternative fate of urate when oxidative stress may overwhelm the regeneration of urate antioxidant capacity. We hypothesize that low plasma urate instead reflects increased oxidation of urate to generate reactive urate radicals that can chemically modify protein lysine residues, altering protein structure or function, a process known as protein uratylation. The balance between urate antioxidant benefit, and urate oxidation to damaging radicals, may uniquely depend on the location and nature of the oxidative stress. In this R03 we are embarking on exploratory studies to better understand why urate therapy may not have been as successful as anticipated. Our goal is to generate and validate new tools that will assist movement disorders researchers in the future in testing the relevance of protein uratylation across a range of preclinical models and human biospecimens.