Rescue of Neuronal Cell Death by ER-stress protein overexpression

通过 ER 应激蛋白过度表达拯救神经元细胞死亡

• 批准号: 15200028
• 负责人: OGAWA Satoshi
• 金额: $ 28.87万
• 依托单位: Graduate School of Medical Science, Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15200028/
• 关键词: Astrocytes; Brain ischemia; ER-stress; Gene Therapy; Glutamic acid; Ischemic tolerance; パーキンソニズム; 小胞体関連蛋白分解; 神経細胞死; ドパミン; 黒質線条体神経; グルタミン酸; 小脳発生; プルキンエ細胞

ORP150 is a novel stress protein localized in the endoplasmic reticulum (ER). To investigate the role of ORP150 in delayed neuronal cell death, we have examined its expression in the gerbil brain after the ischemic insult. The expression of ORP150 antigen, as well as its transcripts, was observed in the CA1 region after the occlusion of the common carotid artery, and this was enhanced by the preconditioning. In cultured neurons, exposure to either hypoxia or glutamate induced the expression of ORP150, and this was also observed by treating the culture with either thapsigargin or breferdin-A, indicating that both glutamate and hypoxia can cause stress in the ER (ER stress). Neurons became more vulnerable to these stresses following treatment of either cycloheximide or the infection with an adenovirus carrying ORP150 antisense structure, In contrast, the overexpression of ORP150 by adenovirus suppressed the neuronal cell death, and this was accompanied by the suppression of the Ca2+ elev … More ation and proteolytic activity induced by glutamate. Further, overexpression of ORP150 in CA1 neurons by the adenovirus carrying ORP150-sense structure suppressed delayed neuronal cell death after ischemia. These date suggest a possible function of ORP150 as an intracellular apparatus, which participates in a protective response in ischemic tolerance.Selective loss of dopaminergic neurons is the final common pathway in Parkinson's disease. We discuss the role of ER-stress in neuronal cell death in SNpc by introducing two models. Upregulation of Pael-Receptor in the substantia nigra pars (SNpc) of mice induces endoplasmic reticulum (ER) stress leading to a decrease in tyrosine hydroxylase and death of dopaminergic neurons. The role of ER stress in dopaminergic neuronal vulnerability was highlighted by their enhanced death in mice deficient in the ubiquitin-protein ligase Parkin and the ER chaperone ORP150, suggesting parkin dysfunction result in ER-stress mediated neuronal cell death. Conversely, transgenic rats overexpressing megsin (Tg meg), a newly identified serine protease inhibitor (serpin), demonstrated intraneuronal periodic-acid Schiff (PAS) positive inclusions, which distributed throughout the deeper layers of cerebral cortex, hippocampal CA1, and substantia nigrta. Enhanced ER stress was observed in dopamine neurons in SNpc, accompanied with loss of neuronal viability and motor coordination. In both subregions, PAS-positive inclusions were also positive with megsin. These data suggest that enhanced ER stress causes selective vulnerability in a set of neuronal populations. Less

ORP150 是一种定位于内质网 (ER) 的新型应激蛋白。为了研究 ORP150 在延迟性神经细胞死亡中的作用，我们检查了沙鼠大脑在缺血性损伤后的表达。颈总动脉闭塞后，在 CA1 区域观察到 ORP150 抗原及其转录物的表达，并且这种表达通过预处理而增强。在培养的神经元中，暴露于缺氧或谷氨酸会诱导 ORP150 的表达，并且通过用毒胡萝卜素或 breferdin-A 处理培养物也观察到这一点，表明谷氨酸和缺氧都会导致 ER 应激（ER 应激）。在使用放线菌酮治疗或感染携带 ORP150 反义结构的腺病毒后，神经元变得更容易受到这些应激的影响。相反，腺病毒过度表达 ORP150 抑制了神经元细胞死亡，并且伴随着谷氨酸诱导的 Ca2+ 升高和蛋白水解活性的抑制。此外，携带 ORP150 有义结构的腺病毒在 CA1 神经元中过度表达 ORP150 抑制了缺血后延迟性神经元细胞死亡。这些数据表明 ORP150 作为细胞内装置的可能功能，参与缺血耐受的保护性反应。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。我们通过引入两个模型来讨论 ER 应激在 SNpc 神经元细胞死亡中的作用。小鼠黑质部 (SNpc) 中 Pael 受体的上调会诱导内质网 (ER) 应激，导致酪氨酸羟化酶减少和多巴胺能神经元死亡。内质网应激在多巴胺能神经元脆弱性中的作用通过在泛素蛋白连接酶 Parkin 和内质网伴侣 ORP150 缺陷的小鼠中的死亡增加而凸显，表明 Parkin 功能障碍导致内质网应激介导的神经元细胞死亡。相反，过度表达megsin（Tg meg）（一种新发现的丝氨酸蛋白酶抑制剂（serpin））的转基因大鼠表现出神经元内高碘酸希夫（PAS）阳性包涵体，分布在大脑皮层、海马CA1和黑质的深层。在 SNpc 的多巴胺神经元中观察到 ER 应激增强，并伴有神经元活力和运动协调性的丧失。在这两个次区域中，PAS 阳性内含物也呈 megsin 阳性。这些数据表明，增强的内质网应激会导致一组神经元群体选择性脆弱。较少的

项目成果

Transmission of cell stress from endoplasmic reticulum to mitochondria: enhanced expression of Lon protease.

• DOI: 10.1083/jcb.200108103
• 发表时间: 2002-06-24
• 期刊: The Journal of cell biology
• 作者: Hori O;Ichinoda F;Tamatani T;Yamaguchi A;Sato N;Ozawa K;Kitao Y;Miyazaki M;Harding HP;Ron D;Tohyama M;M Stern D;Ogawa S
• 通讯作者: Ogawa S

The ER chaperone 150 kDa Oxygen Regulated Protein (ORP150) improves insulin resistance in Type 2 Diabetes Mellitus.

ER 伴侣 150 kDa 氧调节蛋白 (ORP150) 可改善 2 型糖尿病的胰岛素抵抗。

• 发表时间: 2005
• 期刊: Diabetes. 68
• 作者: 小澤;小川;他
• 通讯作者: 他

Accumulation of microglial cells expressing ELR motif-positive CXC chemokines and their receptors CXCR2 in monkey hippocanpus after ischemia-reperfusion.

缺血再灌注后猴海马中表达 ELR 基序阳性 CXC 趋化因子及其受体 CXCR2 的小胶质细胞的积累。

• 发表时间: 2003
• 期刊: Brain Res 970
• 作者: Popivanova BK;Koike K;Tonchev AB;Ishida Y;Kondo T;Ogawa S;Mukaida N;Inoue M;Yamashima T.
• 通讯作者: Yamashima T.

宮城 ほか: "Gene therapy for prostate cancer using the cytosine deaminase/uracil phosphoribosyltransferase suicide system"J Gene Med.. 5. 30-37 (2003)

Miyagi 等：“使用胞嘧啶脱氨酶/尿嘧啶磷酸核糖基转移酶自杀系统进行前列腺癌的基因治疗”J Gene Med.. 5. 30-37 (2003)

北尾 ほか: "ORP15O/HSP12A regulates purkinje cell survival : a role for ER stress in cerebellar development"J.Neurosci.. 24. 1486-1496 (2004)

Kitao 等人：“ORP15O/HSP12A 调节浦肯野细胞存活：ER 应激在小脑发育中的作用”J.Neurosci.. 24. 1486-1496 (2004)