Targeting Innate Immunity as A Therapeutic Intervention for Parkinsons Disease

本提案是对我们目前的退伍军人奖励奖励的更新，重点是了解互动 先天免疫反应与帕金森病(PD)发病机制的关系。我们之前发现 神经元蛋白，α-突触核蛋白(α-SYN)，保护大脑免受病毒感染。使用我们目前的退伍军人管理局 值得支持的是，我们扩展了这些发现，发现α-SYN在神经元中的表达是 神经干扰素刺激基因(ISG)的表达与小胶质细胞激活无关 脑部的急性病毒感染。α-SYN神经元特异性表达缺失导致病毒生长加快 并降低了浸润性细胞毒性T细胞反应的活性。我们延长了 这些发现表明，刺激神经元内特定的RNA感知和信号通路 在依赖αSYN的机制中激活ISG。我们目前的机械学研究奠定了 目前的建议。 对于我们下一阶段的工作和当前退伍军人事务部优秀奖申请的主题，我们希望 了解依赖α的先天免疫反应在帕金森病神经病理进展中的作用。我们的 基本假设是帕金森病是一种先天免疫疾病，对特定先天免疫的抑制 与α-SYN依赖的先天免疫反应相关的通路将抑制PD的进展 病理学。 我们的合作者布伦丁实验室已经开发出一种前驱症状帕金森病小鼠模型 概述了α-SYN病理从小鼠的嗅球扩散到中脑的过程。这项建议 将这种疾病相关模型与靶向敲除或刺激特定先天基因的方法相结合 免疫反应以确定对α-SYN病理、神经退行性变和 大脑中的炎症反应。这三个相互独立、相互关联的目标将提供对 帕金森病潜在的疾病修饰治疗干预。 第一个目标将使用特定先天免疫基因的靶基因敲除来确定 特殊的先天免疫途径在帕金森病病理进展中的作用第二个目标将使用目标 刺激选择先天免疫途径，评估其对帕金森病病理的影响。第三个目标将是 对特定的先天免疫途径使用抑制性抗体，并确定抗体介导的作用 抑制选定的先天免疫途径对帕金森病病理进展的影响。如果这些研究是 如概述的那样完成，我们将确定治疗帕金森病的潜在疾病修改目标。

This proposal is a renewal of our current VA Merit award and is focused on understanding the interactions between innate immune responses and Parkinson’s Disease (PD) pathogenesis. We previously discovered that the neuronal protein, alpha-synuclein (α-syn), protects the brain from viral infections. With our current VA Merit support, we extended these findings to discover that α-syn expression in neurons is required for expression of neuronal interferon stimulated gene (ISG) expression independent of microglial activation during acute viral infection in the brain. Loss of neuron-specific expression of α-syn results in increased virus growth in primary human neurons and decreased activation of infiltrating cytotoxic T-cell responses. We extended these findings to show that stimulation of specific RNA sensing and signaling pathways within neurons activates ISGs in an α-syn-dependent mechanism. Our current mechanistic studies form the foundation for the current proposal. For the next phase of our work and the subject of the current VA merit award application, we want to understand the role of α-syn-dependent innate immune responses in progression of PD neuropathology. Our fundamental hypothesis is that PD is an innate immune disorder and that inhibition of specific innate immune pathways associated with α-syn-dependent innate immune responses will inhibit the progression of PD pathology. The Brundin laboratory, our collaborator, has developed a murine model of prodromal PD that recapitulates the spread of α-syn pathology from the olfactory bulb to the midbrain in mice. This proposal combines this disease relevant model with approaches for targeted knockout or stimulation of specific innate immune responses to determine the effect on propagation of α-syn pathology, neurodegeneration, and inflammatory responses in the brain. The three independent, related aims will provide novel insight into a potential disease-modifying therapeutic intervention for PD. The first aim will use target gene knockout of specific innate immune genes to determine the role of specific innate immune pathways on the progression of PD pathology. The second aim will use targeted stimulation of select innate immune pathways and evaluate the effect on PD pathology. The third aim will employ inhibitory antibodies for specific innate immune pathways and determine the role of antibody-mediated inhibition of selected innate immune pathways on the progression of PD pathology. If the studies are completed as outlined, we will identify potential disease modifying targets for the treatment of PD.