Endoplasmicreticulum(ER)stress and Parkinsonism

内质网（ER）应激与帕金森症

• 批准号: 17500226
• 负责人: KITAO Yasuko
• 金额: $ 2.39万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17500226/
• 关键词: Parkinson's disease; stress; endoplasmic reticulum; neuronal cell death; パーキンソ二ズム; パエル受容体; 小胞体ストレス; 黒質線条体神経; ドパミン; パーキンソニズム; ドパミン「

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

多巴胺能神经元的选择性丢失是帕金森病的最终共同途径，帕金森病是第二种最常见的神经退行性疾病。将携带修饰的神经元特异性启动子和Cre重组酶的腺病毒载体注射到纹状体，实现了PAEL-R在小鼠脑内的选择性神经元表达。逆行感染诱导内质网应激小鼠黑质致密部Pael受体表达上调，导致酪氨酸羟化酶水平降低，多巴胺能神经元死亡。在向SNPC投射/从SNPC投射的其他脑区，未观察到神经细胞死亡。内质网应激在多巴胺能神经元脆弱性中的作用被强调为：在缺乏泛素蛋白连接酶Parkin和内质网伴侣蛋白ORP150(150 kDa氧气调节蛋白)的小鼠中，它们的存活率降低，而由于P…的过度表达，它们的存活率很高更多Arkin或内质网伴侣，78 kDa葡萄糖调节蛋白(GRP78)。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止了parkin基因缺失小鼠的神经元死亡。这些数据提示了一种模型，在该模型中，ER和多巴胺相关的SLAM是与帕金森病相关的多巴胺能神经元存活率下降的主要贡献者。FENIB(伴有神经丝氨酸包涵体的家族性脑病)是由突变的神经丝氨酸在细胞内聚集/聚合引起的。过量表达Megsin(Tg Meg)(一种新发现的丝氨酸蛋白酶抑制物)的转基因大鼠在神经元内发现了PAS阳性包涵体，分布于大脑皮层、海马CA1和黑质的更深层。TG-Meg大鼠海马区提取物显示ER应激蛋白表达增加，caspase-12和-3激活，并伴随着神经元密度的降低。内质网应激在黑质的多巴胺能神经元中也被观察到，同时伴随着神经元存活率和运动协调性的降低。在每种情况下，PAS阳性的包涵体也呈巨蛋白阳性。这些数据表明，Megsin的过度表达导致内质网应激，最终导致PAS阳性包涵体的形成。TG-MEG大鼠提供了一种与FENIB相关的新模型，在该模型中，内质网中蛇毒的聚集导致特定神经元群体的选择性功能障碍/丢失。较少

项目成果

Vaticanol B, a resveratrol tetramer,regulates endoplasmic reticulum (ER)stress and inflammation

Vaticanol B 是一种白藜芦醇四聚体，可调节内质网 (ER) 应激和炎症

• 发表时间: 2007
• 作者: Miura H;et. al.
• 通讯作者: et. al.

Hypoxia-mediated induction of heme oxygenase type I and carbon monoxde release from astrocytes protects nearby cerebral neurons from hypoxia-mediated apoptosis.

缺氧介导的 I 型血红素加氧酶的诱导和星形胶质细胞释放一氧化碳可保护附近的大脑神经元免受缺氧介导的细胞凋亡。

• 发表时间: 2007
• 期刊: Antioxid Redox Signal. 9
• 作者: Imuta N;et. al.
• 通讯作者: et. al.

ピリミジン誘導剤を有効成分とする医薬組成物

含有嘧啶诱导剂作为活性成分的药物组合物

• 发表时间: 2007

A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies).

• DOI: 10.1016/j.bbrc.2006.06.016
• 发表时间: 2006-08
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: K. Takano;Y. Kitao;R. Inagi;T. Momoi;T. Matsuyama;T. Miyata;Y. Yoneda;H. Iso;D. Stern;O. Hori;S. Ogawa

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

• DOI: 10.1093/hmg/ddl439
• 发表时间: 2007-01-01
• 期刊: HUMAN MOLECULAR GENETICS
• 影响因子: 3.5
• 作者: Kitao, Yasuko;Imai, Yuzuru;Ogawa, Satoshi
• 通讯作者: Ogawa, Satoshi