Endoplasmicreticulum(ER)stress and Parkinsonism

多巴胺能神经元的选择性丧失是帕金森病（第二大最常见的神经退行性疾病）的最终共同途径。通过将携带改良的神经元特异性启动子和cree -重组酶的腺病毒载体注射到纹状体中，实现了Parkin相关内皮素样受体（Pael-R）在小鼠脑中的选择性神经元表达。逆行感染诱导的内质网应激上调小鼠黑质部致密部（SNpc）的pael受体，导致酪氨酸羟化酶水平下降和多巴胺能神经元死亡。在SNpc周围的其他脑区未观察到神经元细胞死亡。在泛素蛋白连接酶Parkin和内质网伴侣ORP150（150 kDa氧调节蛋白）缺乏的小鼠中，内质网应激在多巴胺能神经元易损中的作用被强调了出来，与过度表达P…More arkin或ER伴侣78 kDa葡萄糖调节蛋白（GRP78）的小鼠相比，内质网应激在多巴胺能神经元易损中的存活降低。多巴胺相关的毒性也是一个关键因素，因为多巴胺合成酶抑制剂阻断了帕金森氏症小鼠的神经元死亡。这些数据表明，在与帕金森病相关的环境中，内质网和多巴胺相关的slam是多巴胺能神经元活力下降的主要原因。FENIB（家族性脑病与神经蛇形蛋白包涵体）是由突变的神经蛇形蛋白在细胞内积聚/聚合引起的。转基因大鼠过度表达巨噬蛋白（Tg meg），一种新发现的丝氨酸蛋白酶抑制剂（serpin），显示神经元内周期性酸希夫（PAS）阳性包涵体分布在大脑皮层、海马CA1和黑质的更深层。Tg meg大鼠海马提取物显示内质网应激蛋白的表达增加，caspase -12和-3的激活，与神经元密度降低有关。黑质多巴胺能神经元内质网应激增强，同时神经元活力和运动协调性下降。在每个病例中，pas阳性包涵体对megsin也呈阳性。这些数据表明，megsin的过度表达导致内质网应激，最终形成pas阳性包涵体。Tg meg大鼠提供了一种与FENIB相关的新模型，其中内质网中蛇形蛋白的积累诱导了特定神经元群的选择性功能障碍/丧失。少

Selective loss of dopaminergic neurons is the final common pathway in Parkinson's disease, the second most common neurodegenerative disorder. Selective neuronal expression of Pael-R(Parkin associated endothelin-like receptor)in mouse brain was achieved by injecting adenoviral vectors carrying a modified neuron-specific promoter and Cre-recombinase into the striatum. Upregulation of Pael-Receptor in the substantia nigra pars compacts (SNpc) of mice by retrograde infection induced endoplasmic reticulum(ER) stress lead to decreased levels of tyrosine hydroxylase and death of dopaminergic neurons. Neuronal cell death was not observed in the other areas of the brain projecting to/from the SNpc. The role of ER stress in dopaminergic neuronal vulnerability was highlighted by their decreased survival in mice deficient in the ubiquitin-protein ligase Parkin and the ER chaperone ORP150(150 kDa oxygen regulated protein), compared with their robust survival consequent to overexpression of either P … More arkin or an ER chaperone, 78 kDa glucose regulated protein (GRP78). Dopamine-related toxicity was also a key factor, as a dopamine synthetase inhibitor blocked neuronal death in parkin null mice. These data suggest a model in which ER- and dopamine-related slam are major contributors to decreased viability of dopaminergic neurons in a setting relevant to Parkinson's disease.FENIB (familial encephalopathy with neuroserpin inclusion bodies)is caused by intracellular accumulation/polymerization of mutant neuroserpins. Transgenic rats overexpressing megsin (Tg meg), a newly identified serine protease inhibitor (serpin), demonstrated intraneuronal periodic-acid Schiff (PAS)-positive inclusions distributed throughout deeper layers of cerebral cortex, CA1 of the hippocampus, and substantia nigra. Hippocampal extracts from Tg meg rats showed increased expression of ER stress proteins, and activation of caspases-12 & -3, associated with decreased neuronal density. Enhanced ER stress was also observed in dopaminergic neurons in the substantia nigra, in parallel with decreased neuronal viability and motor coordination. In each case, PAS-positive inclusions were also positive for megsin. These data suggest that overexpression of megsin results in ER stress, eventuating in the formation of PAS-positive inclusions. Tg meg rats provide a novel model relevant to FENIB in which accumulation of serpins in the ER induces selective dysfunction/loss of specific neuronal populations. Less