Urate-LRRK2 interactions in Parkinson's disease

尿酸盐-LRRK2在帕金森病中的相互作用

• 批准号: 10427325
• 负责人: MICHAEL A SCHWARZSCHILD
• 金额: $ 38.84万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427325
• 关键词: Address; Albuterol; Animal Model; Antioxidants; Astrocytes; Attenuated; Behavior; Biological Markers; Caffeine; Cell model; Clinical; Coculture Techniques; Corpus striatum structure; Dependence; Development; Disease; Disease model; Drug Targeting; Environmental Exposure; Environmental Risk Factor; Epidemiology; Equilibrium; Foundations; Fumarates; Functional disorder; Genes; Genetic; Government; Human; Idiopathic Parkinson Disease; Induced Mutation; Inflammatory; Inherited; Inosine; Investigation; Investments; Knock-out; LRRK2 gene; Laboratories; Laboratory Study; Lead; Light; Link; Mediating; Mediator of activation protein; Modeling; Modification; Molecular; Multiple Sclerosis; Mus; Mutation; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurons; Onset of illness; Other Genetics; Outcome; Parkinson Disease; Pathogenicity; Pathway interactions; Patients; Penetrance; Persons; Pesticides; Pharmacologic Substance; Phenotype; Phosphotransferases; Play; Positioning Attribute; Process; Property; Reproducibility; Risk; Risk Factors; Role; Safety; Serum; Signal Transduction; Testing; Therapeutic; Toxic effect; Transgenes; Transgenic Organisms; Urate; Urate Oxidase; brain cell; clinical development; clinical practice; clinically relevant; cohort; cost effectiveness; demographics; disorder risk; dopaminergic neuron; drug testing; efficacy trial; epidemiologic data; epidemiology study; experimental study; high risk; in vivo Model; insight; mouse LRRK2 protein; mutant; neurotoxicity; nuclear factor-erythroid 2; overexpression; personalized medicine; protective effect; purine metabolism; response; therapeutic development; urinary

Urate-LRRK2 interactions in Parkinson’s disease Project Summary/Abstract: Although mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common known genetic cause of Parkinson’s disease (PD), their incomplete penetrance indicates that other genetic and environmental factors play important protective roles in LRRK2 PD. Classical epidemiology studies of PD have identified molecular factors that may contribute to or protect against the underlying neurodegenerative process. Among the latter, urate an endogenous antioxidant as well as the end product of purine metabolism has emerged as a major inverse (reduced) risk factor not only for PD onset but also for its clinical progression. A convergence of these epidemiological data with laboratory evidence of its neuroprotective properties suggests that urate may be a mediator as well as a marker of favorable outcomes in idiopathic PD. New biomarker findings of lower urate levels among LRRK2 PD patients compared to people with LRRK2 mutations who have not developed PD raise the possibility that higher levels of endogenous urate contribute to the incomplete penetrance of LRRK2 mutations. The hypothesis is strengthened by evidence that urate protects dopaminergic neurons by activating the Nrf2 antioxidant response pathway, which has recently been implicated in LRRK2 pathophysiology. The current project will determine the neuroprotective potential and molecular mechanisms of urate in laboratory models and human biomarker studies of LRRK2 PD. Through its specific aims (SAs) it will characterize the neuroprotective effects of urate and their astrocyte dependence in cellular and animal models of neurodegeneration in a LRRK2+ PD (SA 1). The role of Nrf2 in the neuroprotective actions of urate and another Nrf2 activator, dimethyl fumarate (a pharmaceutical, approved for disease modification in multiple sclerosis) will be incisively addressed through a complementary set Nrf2 knockout and Nrf2 transgene rescue studies in LRRK2+ PD models (SA 2). Lastly, the interaction between urate and LRRK2 kinase activity (gauged by levels of auto-phosphorylated LRRK2) will be explored in clinical cohorts of idiopathic and LRRK2 PD (SA 3). The mechanistic and clinical insights generated by these studies may validate Nrf2 activation as a promising therapeutic strategy in LRRK2 PD, and may thereby facilitate early steps toward personalized medicine for PD. The results may also help address a growing concern over cost-effectiveness in the field of personalized medicine because Nrf2 activators are already available for clinical use. And of those poised for efficacy trials in LRRK2 PD the urate precursor inosine has been developed as a non-proprietary therapeutic with foundation and government investment. Thus the project offers realistic prospects for advancing our understanding of PD neurobiology and treatment.

尿酸盐-LRRK2在帕金森病中的相互作用 项目摘要/摘要： 尽管编码富含亮氨酸重复激酶 2 (LRRK2) 的基因突变是最常见的 帕金森病 (PD) 的已知遗传原因，其不完全外显率表明其他 遗传和环境因素在 LRRK2 PD 中发挥重要的保护作用。经典流行病学 帕金森病的研究已经确定了可能有助于或预防潜在帕金森病的分子因素。 神经退行性过程。其中，尿酸盐是一种内源性抗氧化剂，也是最终的抗氧化剂。 嘌呤代谢产物已成为主要的反向（减少）危险因素，不仅是帕金森病的主要反向（减少）危险因素 发病率以及其临床进展。这些流行病学数据与实验室数据的融合 其神经保护特性的证据表明尿酸盐可能是一种介质和标记物 特发性 PD 的良好结果。 LRRK2 PD 尿酸水平较低的新生物标志物发现 与未患 PD 的 LRRK2 突变患者相比，这种可能性增加 较高水平的内源性尿酸导致 LRRK2 突变的不完全外显。 有证据表明尿酸盐通过激活多巴胺能神经元来保护多巴胺能神经元，这一假设得到了加强。 Nrf2 抗氧化反应途径，最近与 LRRK2 病理生理学有关。这 当前的项目将确定尿酸盐的神经保护潜力和分子机制 LRRK2 PD 的实验室模型和人类生物标志物研究。通过其具体目标（SA），它将 表征尿酸盐的神经保护作用及其在细胞和动物中的星形胶质细胞依赖性 LRRK2+ PD 神经退行性变模型 (SA 1)。 Nrf2 在神经保护作用中的作用 尿酸盐和另一种 Nrf2 激活剂富马酸二甲酯（一种药物，已批准用于治疗疾病） 多发性硬化症的修饰）将通过补充集 Nrf2 得到彻底解决 LRRK2+ PD 模型中的敲除和 Nrf2 转基因拯救研究 (SA 2)。最后是互动 尿酸盐和 LRRK2 激酶活性（通过自磷酸化 LRRK2 的水平来衡量）之间的关系将 在特发性和 LRRK2 PD (SA 3) 的临床队列中进行了探索。机制和临床见解 这些研究产生的结果可能会验证 Nrf2 激活作为 LRRK2 的一种有前途的治疗策略 PD，从而可能促进针对 PD 个性化医疗的早期步骤。结果也可能 有助于解决个性化医疗领域对成本效益日益增长的担忧，因为 Nrf2激活剂已经可供临床使用。以及那些准备进行 LRRK2 PD 疗效试验的人 尿酸盐前体肌苷已被开发为一种非专有治疗药物，具有基础和 政府投资。因此，该项目为增进我们的理解提供了现实的前景 PD 神经生物学和治疗。