Ryu Elizabeth J, Harding Heather P, Angelastro James M, Vitolo Ottavio V, Ron David, Greene Lloyd A
Department of Pathology, Center for Neurobiology and Behavior, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
J Neurosci. 2002 Dec 15;22(24):10690-8. doi: 10.1523/JNEUROSCI.22-24-10690.2002.
6-hydroxydopamine, 1-methyl-4-phenyl-pyridinium (MPP+), and rotenone cause the death of dopaminergic neurons in vitro and in vivo and are widely used to model Parkinson's disease. To identify regulated genes in such models, we performed serial analysis of gene expression on neuronal PC12 cells exposed to 6-hydroxydopamine. This revealed a striking increase in transcripts associated with the unfolded protein response. Immunoblotting confirmed phosphorylation of the key endoplasmic reticulum stress kinases IRE1alpha and PERK (PKR-like ER kinase) and induction of their downstream targets. There was a similar response to MPP+ and rotenone, but not to other apoptotic initiators. As evidence that endoplasmic reticulum stress contributes to neuronal death, sympathetic neurons from PERK null mice in which the capacity to respond to endoplasmic reticulum stress is compromised were more sensitive to 6-hydroxydopamine. Our findings, coupled with evidence from familial forms of Parkinson's disease, raise the possibility of widespread involvement of endoplasmic reticulum stress and the unfolded protein response in the pathophysiology of this disease.
6-羟基多巴胺、1-甲基-4-苯基吡啶离子（MPP+）和鱼藤酮在体外和体内均可导致多巴胺能神经元死亡，被广泛用于帕金森病的模型构建。为了鉴定此类模型中受调控的基因，我们对暴露于6-羟基多巴胺的神经元PC12细胞进行了基因表达系列分析。这揭示了与未折叠蛋白反应相关的转录本显著增加。免疫印迹证实了内质网应激关键激酶IRE1α和PERK（PKR样内质网激酶）的磷酸化及其下游靶点的诱导。对MPP+和鱼藤酮有类似反应，但对其他凋亡启动剂无反应。作为内质网应激导致神经元死亡的证据，来自PERK基因敲除小鼠的交感神经元对6-羟基多巴胺更敏感，这些小鼠对内质网应激的反应能力受损。我们的发现，再加上家族性帕金森病的证据，增加了内质网应激和未折叠蛋白反应广泛参与该疾病病理生理学的可能性。
