Neuroinflammation and microglial Kv1.3 in Parkinsons disease

帕金森病中的神经炎症和小胶质细胞 Kv1.3

• 批准号: 10528896
• 负责人: Anumantha Gounder Kanthasamy
• 金额: $ 37.35万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528896
• 关键词: Neuroinflammation; microglial; Kv1.3; Parkinsons; disease

A sustained neuroinflammatory insult characterized by massive microglia activation has been well recognized as a major pathophysiological contributor to the progression of neurodegenerative processes in Parkinson’s disease (PD). Interestingly, microglia constitute a particularly attractive therapeutic target for PD because elevated microglia activation is evident during the early stages of PD pathogenesis preceding dopaminergic degeneration. Recent studies pertaining to neuroinflammation in PD have generated tremendous enthusiasm because α-synuclein (αSn) aggregates can serve as an endogenous antigen triggering neurotoxicity by provoking a potent microglia-mediated proinflammatory response. Also, accumulating evidence reveals that misfolded αSyn spreads through a cell-to-cell transmission mechanism, contributing to the propagation of α yn pathology to neighboring neuronal and glial cells, possibly augmenting the progression of PD. Despite these advances, the fundamental neurobiological mechanisms regulating sustained microglia activation and neuroinflammatory cascades during pathogenic αSyn aggregate stimulation remain to be established. Thus, identification of key targets contributing to sustained microglia activation could provide potential targets to slow the progression of the disease. We recently obtained exciting new data showing that the voltage-gated potassium channel Kv1.3 is highly upregulated in aggregated αSyn-stimulated primary microglia and animal models of PD, as well as in human PD postmortem samples. Importantly, patch-clamp electrophysiological studies confirmed that the observed Kv1.3 upregulation translates to increased Kv1.3 channel activity. Additional preliminary results suggest that a proinflammatory kinase PKCδ plays a role in αSyn aggregate-induced Kv1.3 upregulation. To further expand our novel preliminary results, we will systematically pursue the following specific aims: (i) characterize Kv1.3 upregulation and activation of pro-inflammatory microglia in animal models of αSyn aggregate-induced neurotoxicity, and define the role of Kv1.3 in microglia-mediated neuroinflammation and augmentation of the neurodegenerative process in nigrostriatal dopaminergic neurons in PD, (ii) unravel the molecular underpinning of Kv1.3 channel upregulation in microglia during an αSyn aggregate-induced neuroinflammatory insult, and (iii) establish the role of Kv1.3 in mediating the proinflammatory response in the nigrostriatal dopaminergic system during αSyn protein aggregation in animal models of PD. We will use multiple model systems and state-of-the-art biochemical, cellular, neurophysiological, histological and neurochemical approaches to achieve these specific aims. Overall, we anticipate that our proposed studies will provide novel mechanistic insights into sustained microglia activation and its role in neuroinflammatory processes in PD disease progression and will offer novel therapeutic targets to curtail neuroinflammatory responses in PD and other related neurodegenerative disorders.

以大量小胶质细胞激活为特征的持续性神经炎症损伤已被广泛认为是一种 帕金森病 (PD) 神经退行性过程进展的主要病理生理学因素表明，小胶质细胞是帕金森病特别有吸引力的治疗靶点，因为在多巴胺能变性之前的帕金森病发病机制的早期阶段，小胶质细胞的激活是明显的。 PD 引起了极大的热情，因为 α-突触核蛋白 (αSn) 聚集体可以作为内源性抗原，通过激发有效的小胶质细胞介导的促炎症反应来触发神经毒性。越来越多的证据表明错误折叠的 αSyn 会传播 尽管有这些进展，但在致病性 αSyn 过程中调节持续小胶质细胞激活和神经炎症级联反应的基本神经生物学机制。因此，确定有助于小胶质细胞持续激活的关键靶标可能会提供减缓疾病进展的潜在靶标，这些数据表明电压门控钾通道。 Kv1.3 在聚集的 αSyn 刺激的原代小胶质细胞和 PD 动物模型以及人类 PD 死后中高度上调 重要的是，膜片钳电生理学研究证实，观察到的 Kv1.3 上调可转化为 Kv1.3 通道活性增加。其他初步结果表明促炎激酶 PKCδ 在 αSyn 聚集体诱导的 Kv1.3 上调中发挥作用。扩展我们新的初步结果，我们最终将追求以下具体目标：（i）在αSyn聚集体诱导的神经毒性动物模型中表征Kv1.3上调和促炎小胶质细胞的激活，以及定义 Kv1.3 在小胶质细胞介导的神经炎症和 PD 黑质纹状体多巴胺能神经元神经退行性过程增强中的作用，(ii) 揭示在 αSyn 聚集体诱导的神经炎症损伤期间小胶质细胞 Kv1.3 通道上调的分子基础，以及(iii) 确定 Kv1.3 在 αSyn 蛋白作用期间介导黑质纹状体多巴胺能系统促炎反应中的作用我们将使用多种模型系统和最先进的生化、细胞、神经生理学、组织学和神经化学方法来实现这些特定目标，总体而言，我们预计我们提出的研究将提供新颖的机制见解。小胶质细胞持续激活及其作用 帕金森病进展中的神经炎症过程，将为减少帕金森病和其他相关神经退行性疾病的神经炎症反应提供新的治疗靶点。