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The study of modulation of neuronal cell death and searching for new functional molecule regulated by endoplasmic reticulum stress and by innate immune system

研究内质网应激和先天免疫系统调节神经细胞死亡并寻找新的功能分子

基本信息

批准号：
16590040
负责人：
OKUMA Yasunobu
金额：
$ 2.24万
依托单位：
CHIBA INSTITUTE OF SCIENCE (2005)Hokkaido University (2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590040/
关键词：
neuronal cell death ER stress innage immunity chemical chaperon 4-phenylbutylate 脳虚血フェニル酪酸

项目摘要

Recent studies have shown that neurodegenerative disorders such as Alzheimer's and Parkinson's diseases are involved in a disruption of endoplasmic reticulum (ER) function. We investigated the effects of 4-phenylbutylate (4-PBA) on the accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R) pathologically relevant to the loss of dopaminergic neurons in autosomal recessive juvenile Parkinsonism (AR-JP). 4-PBA restored the normal expression of Paer-R protein and suppressed ER stress induced by the accumulation of Paer-R. In addition, we showed that 4-PBA attenuated the activation of ER-stress-induced signal transduction pathways and subsequent neuronal cell death. Furthermore, we revealed that 4-PBA possesses chemical chaperon activity in vitro, which prevents the aggregation of denatured α-lactalbumin and bovine serum albumin (BSA).Epidemiological evidence has shown that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of Parkinson's disease and Alzheimer's disease. However, the mechanism (s) by which NSAIDs elicit their anti-neurodegenerative effects is not clear. We found that pretreatment with aspirin significantly inhibited tunicamycin-induced ER-stress response such as XBP-1 mRNA splicing and induction of GRP78 and CHOP. Furthermore, we demonstrated that aspinin directly inhibited the aggregation of reduced α-lactalbumin and BSA, indicating the possibility that aspirin act as a chemical chaperone.

最近的研究表明，神经退行性疾病如阿尔茨海默病和帕金森病与内质网（ER）功能的破坏有关。我们研究了4-苯基丁酸（4-PBA）对帕金森相关内皮素受体样受体（Pael-R）积累的影响，该受体与常染色体隐性遗传性幼年帕金森病（AR-JP）中多巴胺能神经元的丧失在病理上相关。4-PBA恢复了Paer-R蛋白的正常表达，抑制了Paer-R积累引起的内质网应激。此外，我们发现4-PBA减弱内质网应激诱导的信号转导通路的激活和随后的神经元细胞死亡。此外，我们在体外发现4-PBA具有化学伴侣子活性，可以阻止变性α-乳清蛋白和牛血清白蛋白（BSA）的聚集。流行病学证据表明，非甾体抗炎药（NSAIDs）可降低帕金森病和阿尔茨海默病的风险。然而，非甾体抗炎药引发其抗神经退行性作用的机制尚不清楚。我们发现阿司匹林预处理显著抑制tunicamycin诱导的er应激反应，如XBP-1 mRNA剪接和GRP78和CHOP的诱导。此外，我们发现阿司匹林直接抑制α-乳清蛋白和BSA的聚集，表明阿司匹林可能作为化学伴侣。