Interaction of alpha-synuclein and neurotoxicants with Mac1-NADPH oxidase

描述(申请人提供)：遗传脆弱性和环境暴露都与特发性帕金森病(PD)的发展有关；然而，这两个因素阻断的确切机制仍然难以捉摸。这一建议旨在探索遗传易感性和环境因素之间的潜在联系-小胶质细胞MAC1和NADPH氧化酶之间的紧密耦合，两者都是参与小胶质细胞激活的关键膜蛋白，小胶质细胞激活是神经炎症的标志。小胶质细胞激活的机制尚不完全清楚。虽然神经炎症的一些成分也可以有利于神经元的存活，但促炎因子，特别是活性氧基团(ROS)，当产生过量时，被认为会对中枢神经系统造成“侧枝”损害。MAC1和NADPH氧化酶之间的偶联似乎是导致神经损伤的促炎性ROS的主要来源之一。更重要的是，许多内源性毒素和外源性神经毒物的作用似乎集中在MAC1-NADPH氧化酶途径的激活上。因此，这项建议将集中在这两种蛋白质的偶联上，使用各种体外和体内实验系统，以研究遗传易感性(由突触核蛋白基因突变模拟)通过MAC1-NADPH氧化酶偶联与帕金森病毒物相互作用的详细机制。此外，还将探讨星形胶质细胞对小胶质细胞激活的作用。最后，我们将研究新型和特异性的抑制剂来阻断MAC1和/或NADPH氧化酶，从而提供新的治疗方法来特异性地抑制促炎因子，同时避免神经炎症的神经保护因素，以减缓PD的进展。

DESCRIPTION (provided by applicant): Both genetic vulnerability and environmental exposure have been linked to the development of idiopathic Parkinson's disease (PD); however, the precise mechanisms by which these two factors intercept remain elusive. This proposal is designated to explore a potential link between genetic susceptibility and environmental factors - a tight coupling between microglial Mac1 and NADPH oxidase, both are membrane proteins critically involved in microglial activation which is a hallmark of neuroinflammation. The mechanisms involved in microglial activation are not understood completely. While some components of neuroinflammation can also be beneficial to neuronal survival, pro- inflammatory factors, especially reactive oxygen species (ROS), when produced in excess, are believed to cause "collateral" damage to the central nervous system. The coupling between Mac1 and NADPH oxidase enzyme appears to be one of the major sources of pro-inflammatory ROS causing neural damage. More importantly, the action of many endogenous toxins and exogenous neurotoxicants seems to converge on the activation of Mac1-NADPH oxidase pathway. Thus, this proposal will be centered on the coupling of these two proteins, with the use of various in vitro and in vivo experimental systems, to examine the detailed mechanisms by which genetic susceptibility (modeled by mutations of -synuclein gene) interact with parkinsonian toxicants via Mac1-NADPH oxidase coupling. Additionally, contribution of astroglia to microglial activation will also be explored. Finally, we will investigate novel and specific inhibitors that block Mac1 and/or NADPH oxidase, thereby providing new therapies to inhibit pro-inflammatory factors specifically while sparing neuroprotective elements of neuroinflammation, to slow down the progression of PD.