Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation
Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation
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DOI：
10.1093/hmg/ddl439
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Ogawa, Satoshi
中科院分区：
文献类型：
--
作者：
Kitao, Yasuko;Imai, Yuzuru;Ogawa, Satoshi
多巴胺能神经元的选择性丧失是帕金森病的最终共同途径。通过将携带改良神经元特异性启动子和Cre重组酶的腺病毒载体注入纹状体，实现了Parkin相关内皮素受体样受体（Pael-R）在小鼠脑中的表达。逆行感染诱导内质网应激导致小鼠黑质致密部Pael-R上调，导致多巴胺能神经元死亡。在缺乏泛素蛋白连接酶Parkin和内质网伴侣ORP150 （150 kDa氧调节蛋白）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。多巴胺相关的毒性也是一个关键因素，因为多巴胺合成抑制剂阻断了帕金缺失小鼠的神经元死亡。这些数据表明，内质网和多巴胺相关的应激是帕金森病相关环境中多巴胺能神经元活力下降的主要原因。
Selective loss of dopaminergic neurons is the final common pathway in Parkinson's disease. Expression of Parkin associated endothelin-receptor like receptor (Pael-R) in mouse brain was achieved by injecting adenoviral vectors carrying a modified neuron-specific promoter and Cre recombinase into the striatum. Upregulation of Pael-R in the substantia nigra pars compacta of mice by retrograde infection induced endoplasmic reticulum (ER) stress leads to death of dopaminergic neurons. 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). Dopamine-related toxicity was also a key factor, as a dopamine synthesis inhibitor blocked neuronal death in parkin null mice. These data suggest a model in which ER- and dopamine-related stress are major contributors to decreased viability of dopaminergic neurons in a setting relevant to Parkinson's disease.