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.

项目概要： 帕金森病 (PD) 是世界上第二大常见的神经退行性疾病，超过 1 目前有 100 亿美国人患有帕金森病，65 岁以上的人患帕金森病的风险大大增加。 众所周知，遗传和环境因素都会导致帕金森病的发病。 其中，LRRK2-G2019S 最常见，存在于广泛的种族群体中，占 1-3% 散发性和 4-8% 的家族性 PD 病例然而，LRRK2-G2019S 如何促进 PD 的发病机制。 令人惊讶的是，G2019S 敲入 (KI) 小鼠仅出现 PD 的前期症状， 表明该发病机制需要其他触发因素。我们最近报道了 LRRK2 在其中的关键作用。 最近的一项研究表明，NLRC4 炎症小体的激活和随后 IL-1β 的产生。 血清 IL-1β 水平升高可有效识别无症状 LRRK2-G2019S 携带者与非携带者 在人类中，血清中较高的 IL-1β 浓度预示着人类患 PD 的风险增加 无症状携带者，表明炎症小体激活可能在 PD 发病机制中发挥关键作用。 值得注意的是，大量研究已经确定了 PD 胃肠道的病理生理变化 出现运动症状之前的患者肠道菌群失调的发生率较高， 此外，肠道菌群失调会促进动物模型中 20-90% 的 IBD 患者发生 PD 发病。 有趣的是，最近发现的新的致病性 LRRK2 变异具有较高的风险。 通过 IBD 和 PD，表明 LRRK2 可能在 PD 发病机制中桥接肠-脑轴。 第二次打击诱导的 LRRK2 介导的肠道炎症促进了 PD 外显率 预先倾向的 LRRK2-G2019S KI 模型 我们研究的目的是测试 PD 的“两次打击”模型。 LRRK2-G2019S KI 小鼠的病因学，并通过我们的长期肠脑轴建立新的 PD 模型。 目标是了解 LRRK2 介导的肠脑轴在发病机制中的潜在机制 我们将通过两个具体目标来检验我们的假设： 目标 1，建立角色调查模型。 LRRK2 介导的肠道 NLRC4 炎症小体激活在 PD 发病机制中的作用 目标 2，建立一个模型； 研究 LRRK2 介导的结肠炎在 PD 发病机制中的作用的模型 完成本研究。 该项目将通过肠-脑轴提供新颖的PD模型，以进一步了解LRRK2-的作用 PD 发病机制中介导的肠-脑轴。