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

项目总结： 帕金森病(PD)是世界上第二常见的神经退行性疾病，超过1 目前有100万美国人患有帕金森氏症。65岁以上人群患帕金森病的风险大大增加 好几年了。众所周知，遗传和环境因素都参与了帕金森病的发病。其中 这些，LRRK2-G2019S是最普遍的，在广泛的种族群体中发现，在1%-3%的 散发性和4-8%的家族性帕金森病。然而，LRRK2-G2019S如何促进帕金森病的发病 在很大程度上仍不为人所知。令人惊讶的是，G2019S敲门(KI)小鼠只出现帕金森病的前驱症状， 这表明，发病机制还需要其他触发因素。我们最近报道了LRRK2在 激活NLRC4炎性小体，继而产生IL-1β。最近的一项研究表明， 血清IL-1β水平升高可有效识别无症状LRRK2-G2019S携带者和非携带者 在人类中，血清中较高的IL-1β浓度预示着患帕金森病的风险增加 无症状携带者，提示炎性小体激活可能在帕金森病的发病机制中起关键作用。 值得注意的是，许多研究已经确定了帕金森病患者胃肠道的病理生理变化。 患者在出现运动症状前出现症状。帕金森病患者肠道菌群失调的发生率较高， 在动物模型中，肠道代谢失调促进了帕金森病的发病。此外，IBD患者有20%-90% 发生帕金森病的风险较高。有趣的是，最近的一项发现揭示了新的致病LRRK2变异 IBD和PD的共同作用，提示LRRK2可能在PD发病机制中架起了肠-脑轴之间的桥梁。因此，我们 假设二次电击诱导的LRRK2介导的肠炎症促进帕金森病模型大鼠的帕金森病外显 预置的LRRK2-G2019S KI模型。本研究的目的是检验帕金森病的“两击”模型 LRRK2-G2019S Ki小鼠的病因学研究和建立新的肠脑轴帕金森病模型。我们的长期合作 目的是了解LRRK2介导的肠脑轴在发病机制中的潜在机制。 警局的。我们将用两个具体的目标来检验我们的假设：目标1，建立一个角色调查模型 LRRK2介导的肠道NLRC4炎性小体激活在帕金森病发病中的作用；目的2，建立一种 研究LRRK2介导的结肠炎在帕金森病发病机制中作用的模型。完成这项工作 该项目将通过肠道-脑轴提供新的PD模型，以进一步了解LRRK2- 介导的肠脑轴在帕金森病发病机制中的作用

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.