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: 10640903
• 负责人: MICHAEL A SCHWARZSCHILD
• 金额: $ 38.55万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640903
• 关键词: Acceleration; 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; Link; Mediating; Mediator; 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; neuroprotection; 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.

帕金森病中尿酸与LRRK2的相互作用 项目摘要/摘要： 尽管编码富含亮氨酸的重复蛋白激酶2(LRRK2)的基因突变是最常见的 帕金森病(PD)的已知遗传原因，它们的不完全外显表明其他 遗传和环境因素在LRRK2PD中起着重要的保护作用。经典流行病学 对帕金森病的研究已经确定了可能导致或预防潜在帕金森病的分子因素。 神经退行性变过程。在后者中，尿酸是一种内源性抗氧化剂，也是 嘌呤代谢产物已经成为一个主要的相反(降低)的风险因素，不仅是帕金森病的危险因素 不仅与其发病有关，而且还与其临床进展有关。这些流行病学数据与实验室的汇合 其神经保护特性的证据表明，尿酸盐可能既是一种标志物，也是一种介体。 特发性帕金森病的良好结局。LRRK2 PD患者尿酸水平降低的生物标志物新发现 与未患帕金森病的LRRK2突变患者相比，患者增加了这种可能性 较高水平的内源性尿酸有助于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，这一假设得到了证实。 NRF2抗氧化反应通路，最近被认为与LRRK2的病理生理学有关。这个 目前的项目将确定尿酸盐在脑内的神经保护潜力和分子机制。 LRRK2 PD的实验室模型及人体生物标志物研究通过其具体目标(SA)，它将 尿酸盐的神经保护作用及其对星形胶质细胞依赖性的细胞和动物研究 LRRK2+PD(SA 1)的神经变性模型。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，批准用于疾病 多发性硬化症的修改)将通过互补的集合NRF2来尖锐地解决 LRRK2+PD模型中的基因敲除和Nrf2转基因拯救研究(SA 2)。最后，互动 尿酸盐和LRRK2激酶活性(由自动磷酸化的LRRK2水平衡量)之间的差异将是 在特发性和LRRK2 PD(SA3)的临床队列中进行了探讨。机制和临床洞察力 这些研究产生的结果可能验证Nrf2激活作为LRRK2的一种有前途的治疗策略 帕金森病，并因此可以促进早期步骤的个性化药物治疗帕金森病。结果也可能是 帮助解决个性化医疗领域对成本效益日益增长的担忧，因为 NRF2激活剂已经可用于临床。那些准备在LRRK2 PD进行疗效试验的人 尿酸盐前体肌苷已被开发为一种非专利疗法，其基础和 政府投资。因此，该项目为增进我们对 帕金森病的神经生物学和治疗。

项目成果

Short-term lipopolysaccharide treatment leads to astrocyte activation in LRRK2 G2019S knock-in mice without loss of dopaminergic neurons.

短期脂多糖治疗导致 LRRK2 G2019S 敲入小鼠中的星形胶质细胞活化，且多巴胺能神经元不丢失。

• DOI: 10.21203/rs.3.rs-4076333/v1
• 发表时间: 2024
• 期刊: Research square
• 作者: Ngo,HoangKieuChi;Le,Hoang;Ayer,SamuelJ;Crotty,GraceF;Schwarzschild,MichaelA;Bakshi,Rachit
• 通讯作者: Bakshi,Rachit

The PSG 32nd Annual Symposium on Etiology, Pathogenesis, and Treatment of Parkinson Disease and Other Movement Disorders.

PSG 第 32 届帕金森病和其他运动障碍的病因、发病机制和治疗年度研讨会。

• DOI: 10.1002/mds.29002
• 发表时间: 2022
• 期刊: Movement disorders : official journal of the Movement Disorder Society

Planning for Prevention of Parkinson Disease: Now Is the Time.

• DOI: 10.1212/wnl.0000000000200789
• 发表时间: 2022-08-16
• 期刊: Neurology
• 影响因子: 9.9

What to Test in Parkinson Disease Prevention Trials? Repurposed, Low-Risk, and Gene-Targeted Drugs.

• DOI: 10.1212/wnl.0000000000200238
• 发表时间: 2022-08-16
• 期刊: Neurology
• 影响因子: 9.9

The STEPWISE study: study protocol for a smartphone-based exercise solution for people with Parkinson's Disease (randomized controlled trial).

• DOI: 10.1186/s12883-023-03355-8
• 发表时间: 2023-09-12
• 期刊: BMC NEUROLOGY
• 影响因子: 2.6
• 作者: Schootemeijer, Sabine;de Vries, Nienke M.;Macklin, Eric A.;Roes, Kit C. B.;Joosten, Hilde;Omberg, Larsson;Ascherio, Alberto;Schwarzschild, Michael A.;Bloem, Bastiaan R.
• 通讯作者: Bloem, Bastiaan R.