Neuron death in Parkinson's disease: The role of Trib3

这项拟议的研究的最终目标是创造出阻止神经元进化的创新方法 帕金森氏病(PD)中的变性。目前的治疗方法可以缓解帕金森病的症状，但不能缓解其 因此，主要需要新的想法和方法来减缓或阻止无情的 神经细胞变性在这种疾病中发生的神经元退化这里的核心思想是，无论发起人是谁 帕金森病、神经元变性和死亡的原因是共享的远端促死亡调节失调所致 靶向这些通路和/或其组件具有阻止或延缓疾病的潜力 进步。这次更新继续关注Trib3蛋白。我们的发现表明，Trib3是 由与帕金森病相关的多种细胞应激诱导，并在黑质多巴胺能区升高 帕金森病患者的神经元以及帕金森病的多种细胞模型。Trib3既是充分也是必要的 促进帕金森病细胞模型中神经元的变性和死亡及其缺失或抑制 模型提供了防止轴突退化和死亡的保护。对上游监管的审视 帕金森病模型中Trib3的诱导途径揭示了转录因子ATF4和ATF4的必要参与 CHOP/DDIT3和初步数据表明，药物“Adaptaquin”对这一途径的干扰可阻断 Trib3诱导与细胞PD模型中神经元的死亡和变性。关于机理，我们的研究 表明Trib3与Parkin(一种神经保护性蛋白，其丢失或功能障碍导致早期 人类帕金森病的发病形式以及细胞和动物模型中的神经元变性)在活细胞中，这 结合通过COP1E3连接酶导致Parkin耗竭。这些发现导致了一种假设，即 启动帕金森病神经元变性和死亡途径的慢性细胞应激使Trib3升高 这导致了疾病缓慢而不可阻挡的发展，至少部分是通过 帕金的级别越来越低。利用这些观察结果，以进一步将Trib3作为目标 为了缓解帕金森病的进展，提出了3个具体目标。这些是：1)测试 活体小鼠黑质多巴胺能神经元中Trib3有条件缺失的假说 在帕金森氏症模型中提供保护。PD模型将包括6-OHDA和a-OHDA的治疗- 突触核蛋白过度表达/暴露于a-突触核蛋白纤维。2)检验Trib3对 帕金森病患者神经元死亡与保护蛋白Parkin和TO相互作用并耗尽神经元水平 定义这种互动的基础，以便提供策略来破坏这种潜在的关联 治疗目的。3)检验药物“Adaptaquin”对Trib3诱导的干扰假设 将保护帕金森病细胞和动物模型中的神经元。这些研究的成功结果将促进 开发一种针对Trib3的治疗方法，改变帕金森病退行性进展的进程。

The ultimate goal of the proposed research is to create innovative means to halt the progression of neuron degeneration in Parkinson's disease (PD). Present treatments alleviate the symptoms of PD, but not its advancement and there is therefore a major need for new ideas and approaches to slow or stop the relentless degeneration of neurons that occurs in this disorder. The core idea here is that irrespective of the initiating causes of PD, neuron degeneration and death are promoted by dysregulation of shared distal pro-death pathways and that targeting these pathways and/or their components has the potential to stop or slow disease progression. This renewal continues to focus on the protein Trib3. Our findings have shown that Trib3 is induced by multiple cellular stresses associated with PD and is elevated in dopaminergic substantia nigral neurons of PD patients as well as in multiple cellular models of PD. Trib3 is both sufficient and necessary to promote neuron degeneration and death in cellular models of PD and its deletion or suppression in such models provides protection from neurite degeneration and death. Examination of the upstream regulatory pathway of Trib3 induction in PD models reveals necessary involvement of the transcription factors ATF4 and CHOP/DDIT3 and preliminary data show that interference with this pathway by the drug “adaptaquin” blocks Trib3 induction and neuron death and degeneration in cellular PD models. Regarding mechanism, our studies show that Trib3 interacts with Parkin (a neuroprotective protein whose loss or dysfunction leads to an early onset form of PD in humans and to neuron degeneration in cell and animal models) in living cells and that this association leads to Parkin depletion via the COP1 E3 ligase. These findings lead to the hypothesis that the chronic cellular stresses that initiate the path towards neuron degeneration and death in PD elevate Trib3 expression and that this contributes to the slow and inexorable progression of the disease at least in part by diminishing levels of Parkin. To exploit these observations so as to move forward towards targeting Trib3 for the purpose of alleviating the progression of PD in patients, 3 specific aims are proposed. These are: 1) To test the hypothesis that conditional deletion of Trib3 in substantia nigral dopaminergic neurons of living mice will provide protection in models of Parkinson's disease. PD models will include treatment with 6-OHDA and a- synuclein over-expression/exposure to a-synuclein fibrils. 2) To test the hypothesis that Trib3 contributes to neuron death in PD by interacting with and depleting neuronal levels of the protective protein Parkin and to define the bases for this interaction so as to provide strategies to disrupt this association for potential therapeutic purposes. 3) To test the hypothesis that interference with Trib3 induction by the drug “adaptaquin” will protect neurons in cellular and animal models of PD. The successful outcome of these studies will promote development of a Trib3-targeted therapy that alters the course of degenerative progression in PD.