LRRK2 and inflammasome pathway in Parkinson's disease

摘要： 编码LRRK2(Leucine Rich Repeat Kinase 2)蛋白的LRRK2基因是高血压的主要危险因素。 帕金森病(PD)和LRRK2基因突变导致遗传性和散发性帕金森氏病。 有趣的是，LRRK2基因还增加了克罗恩病和麻风病的风险，而LRRK2是 表达于免疫细胞、神经元和神经胶质细胞。我们最近发现LRRK2与类NOD相互作用 受体(NLR)传感器家族蛋白(NLRPs)、NLRP1和NLRP3。NLRP蛋白是先天发育的关键介体 免疫力，是炎症体的组成部分。我们建议检验突变的LRRK2 与NLRP3和NLRP1-炎症体相互作用并激活，导致小胶质细胞激活和 神经退行性变是帕金森病的病理基础。在目标1中，我们将描述LRRK2与LRRK2的相互作用 NLRP1和NLRP3的体外和体内实验。在目标2中，我们将研究突变体LRRK2是否激活NLRP3- Informmasome参与小胶质细胞的激活，在体外和体内导致神经炎症和变性。在……里面 Aim3，我们将检查突变的LRRK2是否激活神经元中的NLRP1-炎症体，导致 神经退行性变。这些研究将阐明LRRK2连接的炎症体途径的机制 神经退行性变和免疫功能障碍。它们也可能对其他神经学有更广泛的影响 与神经炎症相关的疾病。NLRP/LRRK2信号通路在帕金森病发病中的作用 可能揭示潜在的生物标志物，并可能为疾病修饰的开发提供新的靶点 治疗策略。因此，这个项目有可能产生重大影响，并使那些遭受 帕金森病和其他神经退行性疾病。

Abstract: The LRRK2 locus, coding for the LRRK2 (Leucine Rich Repeat Kinase 2) protein, is a major risk factor for Parkinson’s disease (PD), and mutations in the LRRK2 gene contribute to both genetic and sporadic PD. Intriguingly, the LRRK2 locus also confers increased risk for Crohn’s disease and leprosy, and LRRK2 is expressed in immune cells, neurons and glia. We recently discovered that LRRK2 interacts with NOD-like receptor (NLR) sensor family proteins (NLRPs), NLRP1 and NLRP3. NLRP proteins are key mediators of innate immunity, and are components of inflammasomes. We propose to test the hypothesis that mutant LRRK2 interacts with and activates the NLRP3- and NLRP1-inflammasomes leading to microglial activation and neurodegeneration contributing to PD pathology. In Aim 1, we will characterize the interaction of LRRK2 with NLRP1 and NLRP3 in vitro and in vivo. In Aim 2, we will investigate whether mutant LRRK2 activates the NLRP3- infammasome in microglial activation, leading to neuroinflammation and degeneration in vitro and in vivo. In Aim3, we will examine whether mutant LRRK2 activates the NLRP1-inflammsome in neurons, resulting in neurodegeneration. These studies will elucidate mechanisms underlying LRRK2-linked inflammasome pathway in neurodegeneration and immune dysfunction. They may also have broader implications for other neurological diseases related to neuroinflammation. The understanding of NLRP/LRRK2-linked pathways in PD pathogenesis may reveal potential biomarkers, and may provide novel targets for development of disease-modifying therapeutic strategies. Thus, this project has the potential for significant impact, and benefits those suffering from PD and other neurodegenerative diseases.