Endoplasmic Reticulum Stress and Parkinson's Disease

描述(由申请人提供) 最近的观察表明，蛋白质的异常构象是 多巴胺能神经元的正常成分参与了这种死亡。 帕金森病(PD)的细胞类型。一些罕见形式的帕金森病可能与 导致这种蛋白毒性的突变，要么直接通过影响 将其转化为蛋白毒素的蛋白质的一级结构(例如a-SYN 突变)或间接地，通过影响细胞过程来影响 蛋白毒素的积累(例如PARK2突变)。然而，这种突变 只在一小部分帕金森病患者中发现，这引发了一个问题： 蛋白毒性在其他情况下被触发。我们实验室最近的实验 表明6-羟基多巴胺和鱼藤酮，毒素在实验中被牵连 和环境PD之间，造成折叠能力的失衡 内质网(ER)及其上客户蛋白的负荷 细胞器(所谓的内质网应激)。未补偿的内质网应激可促进 泛素蛋白酶体竞争有限能力引起的蛋白毒性 系统，并通过产生可以改变蛋白质结构的ROS。神经元是 天然易受内质网压力，因为它们广泛的分泌活动和 因为他们高度精细的膜封闭过程，这必须是 由客户蛋白质的高内质网运输率维持。急诊室压力是 正常情况下被未折叠蛋白反应(UPR)抵消，适应性 由内质网应激特异性激活的细胞信号通路。 受损的UPR信号使细胞对内质网的影响特别敏感 压力。因此，我们建议测试内质网应激在发育中的作用 通过检测UPR中损害信号的突变对PD的影响 建立了实验性帕金森病模型和遗传性帕金森病的一个组成部分。我们 将确定在缺乏关键UPR基因的小鼠中，PERK多巴胺能神经元 对6-羟基多巴胺过敏。我们将设法找出 6-羟基多巴胺所赋予的内质网功能，如果可能，将其与 已知的毒素抑制线粒体复合体-1的能力。最后，我们会 认真研究PARK2的S在内质网相关蛋白质降解中的作用。如果 这些实验支持内质网应激在帕金森病发生发展中的作用。 这将影响我们对黄斑狼疮发病机制的思维模式的转变。 这种常见的疾病。

DESCRIPTION (provided by applicant) Recent observations suggest that abnormal conformations of proteins that are normal constituents of the dopaminergic neuron participate in death of this cell type in Parkinson Disease (PD). Some rare forms of PD can be linked to mutations that cause such proteotoxicity, either directly by affecting the primary structure of the protein converting it to a proteotoxin (e.g. a-SYN mutations) or indirectly, by affecting cellular processes that impact on the accumulation of proteotoxins (e.g. PARK2 mutations). However, such mutations are found in only a small fraction of PD patients, raising the question of how proteotoxicity is triggered in other cases. Recent experiments from our lab indicate that 6-hydroxydopamine and Rotenone, toxins implicated in experimental and environmental PD, cause an imbalance between the folding capacity of the endoplasmic reticulum (ER) and the load of client proteins placed on that organelle (so called ER stress). Uncompensated ER stress can promote proteotoxicity by competing for limited capacity of the ubiquitin proteasomal system and by producing ROS that can alter protein structure. Neurons are naturally prone to ER stress because of their extensive secretory activity and because of their highly elaborate membrane enclosed processes, which must be maintained by high rates of ER trafficking of client proteins. ER stress is normally counteracted by the unfolded protein response (UPR), an adaptive cellular signaling pathway that is activated specifically by ER stress. Impaired UPR signaling sensitizes cells specifically to the effect of ER stress. Therefore, we propose to test the role of ER stress in the development of PD by examining the effect of mutations that impair signaling in the UPR on an established model of experimental PD and on a component of genetic PD. We will determine if in mice lacking the key UPR gene, PERK dopaminergic neurons are hypersensitive to 6-hydroxydopamine. We will seek to identify the defect in ER function imparted by 6-hydroxydopamine and relate it, if possible, to the known ability of the toxin to inhibit mitochondrial complex-1. Finally, we will critically examine PARK2's role in ER-associated degradation of proteins. If the proposed experiments support a role for ER stress in the development of PD, this will effect a paradigmatic shift in our thinking about the pathogenesis of this common disorder.