Roles for astrocytic RIPK3 signaling in Parkinson's disease pathogenesis

摘要 帕金森氏病（PD）是一种全球关注的神经退行性疾病，估计花费52美元 仅在美国，每年就有10亿美元。PD的病理学特征包括使人衰弱的运动缺陷， 由黑质纹状体通路中多巴胺能神经元的进行性变性驱动，黑质纹状体通路是 运动功能新出现的证据表明，神经炎症是一个关键的球员在病理生理学的 这个退化的过程。星形胶质细胞是中枢神经系统（CNS）中最丰富的胶质细胞， 在那里它们发挥着各种各样的自我平衡功能。然而，在炎症刺激后，星形胶质细胞进入 一种反应状态，可能是神经毒性的，导致神经元细胞死亡。大量研究表明 反应性星形胶质细胞可能导致临床神经退行性疾病。然而，通过 哪些稳态星形胶质细胞变得具有反应性需要进一步研究。这项建议的主要目的是 是为了确定在以下情况下促进星形胶质细胞活化的细胞和分子机制： 神经变性我们实验室和其他人最近的工作已经确定了受体相互作用蛋白 激酶-3（RIPK 3）作为神经炎症的中枢介质。在此，我们假设炎症性RIPK 3 信号传导可以诱导星形胶质细胞活化，导致下游神经毒性作用和神经元损失。 中脑为了验证这一假设，我将利用新的小鼠遗传系统，其中RIPK 3可以特异性地 在星形胶质细胞中缺失、过表达或选择性激活。目标1中的研究将研究RIPK 3活性如何 在星形胶质细胞形状转录和功能反应与神经毒性星形胶质细胞活化。 目的2将研究星形胶质细胞RIPK 3信号传导是否可以驱动PD发病机制的关键分子特征， 包括多巴胺能轴突变性和纹状体中多巴胺释放的减少。所有这些 实验旨在确定RIPK 3信号传导作为神经毒性星形胶质细胞活化的重要机制，并建立 在PD的病理生理学中的作用。识别这些细胞类型特异性分子机制 帕金森病神经变性的研究对于开发靶向PD疗法至关重要。

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder of global concern, imposing an estimated cost of $52 billion per year in the United States, alone. The pathological hallmarks of PD include debilitating motor deficits, driven by progressive degeneration of dopaminergic neurons in the nigrostriatal pathway, an essential circuit for motor function. Emerging evidence suggests that neuroinflammation is a key player in the pathophysiology of this degenerative process. Astrocytes are the most abundant glial cells in the central nervous system (CNS), where they serve diverse homeostatic functions. However, following inflammatory stimulation, astrocytes enter a reactive state that can be neurotoxic, resulting in neuronal cell death. Numerous studies have now revealed that reactive astrocytes can contribute to clinical neurodegenerative diseases. However, the mechanism through which homeostatic astrocytes become reactive require further investigation. The central purpose of this proposal is to identify cellular and molecular mechanisms that promote astrocyte activation in the context of neurodegeneration. Recent work from our laboratory and others has identified receptor-interacting protein kinase-3 (RIPK3) as a central mediator of neuroinflammation. Here, we hypothesize that inflammatory RIPK3 signaling can induce astrocyte activation, leading to downstream neurotoxic effects and neuron loss in the midbrain. To test this hypothesis, I will utilize novel mouse genetic systems in which RIPK3 can be specifically deleted, overexpressed, or selectively activated in astrocytes. Studies in Aim 1 will examine how RIPK3 activity in astrocytes shapes transcriptional and functional responses associated with neurotoxic astrocyte activation. Aim 2 will examine whether astrocytic RIPK3 signaling can drive key molecular features of PD pathogenesis, including dopaminergic axon degeneration and reduction of dopamine release in the striatum. Together, these experiments aim to identify RIPK3 signaling as a vital mechanism of neurotoxic astrocyte activation and establish roles for this pathway in the pathophysiology of PD. Identifying these cell type-specific molecular mechanisms of Parkinsonian neurodegeneration are of vital importance for developing targeted PD therapeutics.