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性损伤已被公认为是神经系统的一种损伤。 帕金森氏病（PD）神经退行性过程进展的主要病理生理因素。有趣的是，小胶质细胞构成了一个特别有吸引力的治疗目标，因为升高的小胶质细胞激活是明显的PD发病机制的早期阶段之前多巴胺能变性。最近关于PD神经炎症的研究产生了巨大的热情，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反应引发神经毒性。此外，越来越多的证据表明，错误折叠的α-Syn传播 通过细胞间传递机制，促进α yn病理向邻近神经元和神经胶质细胞的传播，可能加速PD的进展。尽管取得了这些进展，但在致病性αSyn聚集体刺激期间调节持续小胶质细胞活化和神经炎症级联反应的基本神经生物学机制仍有待建立。因此，鉴定有助于持续小胶质细胞活化的关键靶点可以提供减缓疾病进展的潜在靶点。我们最近获得了令人兴奋的新数据，表明电压门控钾通道Kv1.3在聚集的α Syn刺激的原代小胶质细胞和PD动物模型中以及在人PD死后高度上调。 样品重要的是，膜片钳电生理学研究证实，所观察到的Kv1.3上调转化为增加的Kv1.3通道活性。其他初步结果表明，促炎激酶PKCδ在αSyn聚集体诱导的Kv1.3上调中起作用。为了进一步扩展我们的新的初步结果，我们将系统地追求以下具体目标：（i）表征αSyn聚集体诱导的神经毒性的动物模型中促炎性小胶质细胞的Kv1.3上调和活化，并确定Kv1.3在PD中小胶质细胞介导的神经炎症和黑质纹状体多巴胺能神经元中神经变性过程的增强中的作用，（ii）阐明αSyn聚集体诱导的神经炎症损伤过程中小胶质细胞Kv1.3通道上调的分子基础，以及（iii）在PD动物模型中建立Kv1.3在αSyn蛋白聚集过程中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物化学，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。总的来说，我们预计我们提出的研究将为持续的小胶质细胞激活及其在 PD疾病进展中的神经炎症过程，并将提供新的治疗靶点，以减少PD和其他相关神经退行性疾病中的神经炎症反应。