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， 多巴胺能神经元的正常成分参与这种死亡。 帕金森病（PD）的细胞类型。一些罕见的PD形式可能与 突变，导致这种蛋白毒性，无论是直接影响 将其转化为蛋白毒素（例如α-SYN）的蛋白质的一级结构 突变）或间接地，通过影响细胞过程， 蛋白毒素的积累（例如PARK 2突变）。然而，这种突变 仅在一小部分PD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，实验中涉及毒素 和环境PD，导致折叠能力之间的不平衡， 内质网（ER）和置于其上的客户蛋白质负载 细胞器（所谓的ER应激）。未补偿的内质网应激可以促进 通过竞争泛素蛋白酶体的有限能力的蛋白毒性 系统和产生ROS，可以改变蛋白质结构。神经元是 由于其广泛的分泌活性， 由于它们高度复杂的膜封闭过程， 通过客户蛋白的高ER运输率维持。ER应力是 通常由未折叠蛋白质反应（UPR）抵消，适应性 细胞信号通路，特别是激活内质网应激。 受损的UPR信号传导使细胞特异性地对ER的作用敏感 应力因此，我们建议测试ER应激在发育中的作用， 通过检查损害UPR信号传导的突变对PD的影响， 建立实验性PD模型和遗传性PD的一个组成部分。我们 将确定在缺乏关键UPR基因的小鼠中， 对6-羟多巴胺过敏我们会设法找出 6-羟基多巴胺赋予的ER功能，如果可能的话， 该毒素抑制线粒体复合物-1的已知能力。最后我们将 严格检查PARK 2在ER相关蛋白质降解中的作用。如果 所提出的实验支持ER应激在PD发展中的作用， 这将影响我们对糖尿病发病机制的思维范式转变， 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.