Understanding the role of LRRK2 G2019S-mediated gut-brain axis in the pathogenesis of Parkinson's disease

了解 LRRK2 G2019S 介导的肠脑轴在帕金森病发病机制中的作用

• 批准号: 10584197
• 负责人: Zizhen Kang
• 金额: $ 42.49万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10584197
• 关键词: Acute; American; Animal Model; Bacterial Infections; Brain; Cells; Chemicals; Chronic; Cohort Studies; Colitis; DNA Sequence Alteration; Development; Disease; Disease model; Enteral; Environment; Environmental Risk Factor; Ethnic group; Etiology; Exhibits; Gastrointestinal tract structure; Genetic; Goals; Human; Immune; Immune response; Impairment; Incidence; Individual; Infection; Inflammasome; Inflammation; Inflammatory Bowel Diseases; Interleukin-1 beta; Investigation; Kidney; Knock-in; Knock-in Mouse; LRRK2 gene; Lung; Mediating; Modeling; Mus; Mutation; Neurodegenerative Disorders; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathogenicity; Patients; Penetrance; Persons; Pharmaceutical Preparations; Phosphotransferases; Play; Population Study; Production; Proteins; Reporting; Research; Risk; Role; Salmonella typhimurium; Serum; Signal Transduction; Symptoms; System; Testing; Translations; Variant; autoinflammatory; cilium biogenesis; dysbiosis; exome sequencing; gain of function; gastrointestinal infection; genetic variant; genome wide association study; gut dysbiosis; gut inflammation; gut-brain axis; high risk; human old age (65+); motor symptom; mutant; novel; pathogen; population based

Project Summary: Parkinson’s disease (PD) is the second most common neurodegenerative disorder in the world, with over 1 million Americans currently suffering from PD. The risk of PD increases greatly in people over the age of 65 years. Both genetic and environmental factors are known to contribute to the pathogenesis of PD. Among these, LRRK2-G2019S is the most prevalent, being found in a wide range of ethnic groups and in 1-3% of sporadic and 4-8% of familial PD cases. However, how LRRK2-G2019S promotes the pathogenesis of PD remains largely unknown. Surprisingly, G2019S knockin(KI) mice only develop pre-symptoms of PD, suggesting other triggers are needed for the pathogenesis. We recently reported a crucial role for LRRK2 in the activation of NLRC4 inflammasome and subsequent production of IL-1β. A recent study showed that increased serum levels of IL-1β effectively identified asymptomatic LRRK2-G2019S carriers from noncarriers in humans and higher IL-1β concentration in the serum predicted increased risk for developing PD among the asymptomatic carriers, suggesting that inflammasome activation might play critical roles in PD pathogenesis. Of note, numerous studies have identified pathophysiological changes in the gastrointestinal tract in PD patients preceding the development of motor symptoms. PD patients have higher incidence of gut dysbiosis, and gut dysbiosis promotes PD pathogenesis in animal models. Furthermore, IBD patients have 20–90% higher risk of developing PD. Intriguingly, a recent finding unraveled novel pathogenic LRRK2 variants shared by both IBD and PD, suggesting LRRK2 might bridge the gut-brain axis in PD pathogenesis. We thus hypothesize that second hit-induced LRRK2-mediated intestinal inflammation promotes the PD penetrance in the predisposed LRRK2-G2019S KI model. The objective of our study is to test the “two-hit” model for PD etiology in LRRK2-G2019S KI mice and establish novel PD models through gut-brain axis. Our long-term goal is to understand the underlying mechanisms of the LRRK2-mediated gut-brain axis in the pathogenesis of PD. We will test our hypothesis with two specific aims: Aim 1, Establish a model for investigation of the role of LRRK2-mediated enteric NLRC4 inflammasome activation in the pathogenesis of PD; Aim 2, Establish a model for investigation of the role of LRRK2-mediated colitis in the pathogenesis of PD. Completion of this project will provide novel PD models through gut-brain axis for further understanding of the role of LRRK2- mediated gut-brain axis in the pathogenesis of PD.

项目摘要： 帕金森氏病（PD）是世界上第二常见的神经退行性疾病，有1个以上 目前有百万美国人患有PD。 PD的风险在65岁以上的人中增加了很大 年。已知遗传因素和环境因素都有助于PD的发病机理。之中 这些，LRRK2-G2019是最普遍的 零星和4-8％的家族性PD病例。但是，LRRK2-G2019S如何促进PD的发病机理 仍然是未知的。令人惊讶的是，G2019S敲蛋白（Ki）小鼠仅出现PD的胞症状， 提示发病机理需要其他触发因素。我们最近报道了LRRK2在 NLRC4炎性体的激活和随后产生IL-1β。最近的一项研究表明 IL-1β的血清水平升高有效地鉴定出非载流子的无症状LRRK2-G2019S载体 在人类中，血清中较高的IL-1β浓度预测，在 无症状的载体表明炎性体激活可能在PD发病机理中起关键作用。 值得注意的是，许多研究已经确定了PD胃肠道的病理生理变化 运动症状发育之前的患者。 PD患者患有肠道营养不良的事件较高， 肠道营养不良促进动物模型中的PD发病机理。此外，IBD患者的患者为20-90％ 开发PD的风险更高。有趣的是，最近发现的新型病原LRK2变体共享了 通过IBD和PD，这表明LRRK2可能会在PD发病机理中桥接肠道轴。我们这样 假设第二次HIT诱导的LRRK2介导的肠炎促进了PD的渗透率 倾向的LRRK2-G2019S KI模型。我们研究的目的是测试PD的“两击”模型 LRRK2-G2019S KI小鼠中的病因，并通过肠脑轴建立新型PD模型。我们的长期 目的是了解发病机理中LRRK2介导的肠道轴的潜在机制 PD。我们将以两个具体的目的检验我们的假设：AIM 1，建立一个研究角色的模型 PD发病机理中LRRK2介导的肠NLRC4炎性体激活；目标2，建立一个 LRRK2介导的结肠炎在PD发病机理中的作用的投资模型。完成此操作 项目将通过肠脑轴提供新型的PD模型，以进一步了解LRRK2-的作用 PD发病机理中介导的肠道轴。