Wang Hua-Qin, Takahashi Ryosuke
Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Antioxid Redox Signal. 2007 May;9(5):553-61. doi: 10.1089/ars.2006.1524.
Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD remains incompletely understood. Environmental factors, oxidative damage, misfolded protein aggregates, ubiquitin-proteasome system impairment, and mitochondrial dysfunction might all be involved. Recent studies point to activation of endoplasmic reticulum (ER) stress-mediated cell death linked to PD. Accumulation of unfolded and/or misfolded proteins in the ER lumen induces ER stress. To withstand such potentially lethal conditions, intracellular signaling pathways collectively termed the unfolded protein responses (UPR) are activated. The UPR include translational attenuation, induction of ER resident chaperones, and degradation of misfolded proteins through the ER-associated degradation. In case of severe and/or prolonged ER stress, cellular signals leading to cell death are activated. Accumulating evidence suggests that ER stress induced by aberrant protein degradation is implicated in PD. Here the authors review the emerging role of ER stress in PD and related disorders, and highlight current knowledge in this field that may reveal novel insight into disease mechanisms and help to provide novel avenues to potential therapies.
帕金森病（PD）是第二常见的神经退行性疾病，其特征是多巴胺能神经元选择性丧失以及路易小体的存在。PD的发病机制仍未完全明确。环境因素、氧化损伤、错误折叠的蛋白质聚集体、泛素 - 蛋白酶体系统损伤以及线粒体功能障碍可能都与之有关。最近的研究指出内质网（ER）应激介导的细胞死亡激活与PD相关。内质网腔中未折叠和/或错误折叠蛋白质的积累会诱导内质网应激。为了抵御这种潜在的致命状况，统称为未折叠蛋白反应（UPR）的细胞内信号通路被激活。UPR包括翻译衰减、内质网驻留伴侣蛋白的诱导以及通过内质网相关降解对错误折叠蛋白质的降解。在严重和/或长期内质网应激的情况下，导致细胞死亡的细胞信号被激活。越来越多的证据表明，异常蛋白质降解诱导的内质网应激与PD有关。在此，作者综述了内质网应激在PD及相关疾病中的新作用，并强调了该领域的当前知识，这些知识可能揭示对疾病机制的新见解，并有助于提供潜在治疗的新途径。
