Novel function of sigma-1 receptor and therapeutics strategy for neurodegenerative disorders

sigma-1受体的新功能及神经退行性疾病的治疗策略

• 批准号: 24659024
• 负责人: FUKUNAGA KOHJI
• 金额: $ 2.5万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2012
• 资助国家: 日本
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-24659024/
• 关键词: 筋萎縮性側索硬化症; シグマー１受容体; ミトコンドリア障害; 小胞体ストレス; メチルピルビン酸; ALS治療薬; 筋萎縮側索硬化症; sigma-1 受容体; TDP-43; TCA 回路; ピルビン酸; Sigma-1受容体; IP3 受容体; 脳血管性認知症; 抗うつ薬

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder caused by motor neuron dysfunction. Recently, a E102Q mutation in the chaperone protein sigma-1 receptor (R) was discovered in familial ALS patients. Here, we address mechanisms underlying neurodegeneration caused by this mutation using overexpression analysis in neuro2A cells. Sigma-1R(E102Q) overexpression promoted its dissociation from the endoplasmic reticulum (ER) membrane and its cytoplasmic aggregation, and in turn impaired mitochondrial ATP production. Under ER stress condition, sigma-1R(E102Q) overexpression aggravated mitochondrial damage, thereby causing apoptosis. The enhancement of ATP production by methyl pyruvate treatment rescued mitochondrial damage induced by sigma-1R(E102Q) overexpression. Taken together, phenotypes observed in sigma-1R(E102Q)-overexpressing cells suggest that ATP supplementation by methyl pyruvate is potential therapeutic strategy to treat ALS caused by sigma-1R mutations.

肌萎缩性侧性硬化症（ALS）是由运动神经元功能障碍引起的神经退行性疾病。最近，在家族性ALS患者中发现了伴侣蛋白Sigma-1受体（R）中的E102Q突变。在这里，我们解决了使用神经2a细胞中的过表达分析引起的神经变性的机制。 Sigma-1r（E102Q）过表达促进了其与内质网（ER）膜及其细胞质聚集的解离，进而损害了线粒体ATP的产生。在ER应力条件下，Sigma-1r（E102Q）过表达加剧了线粒体损伤，从而导致凋亡。通过丙酮酸甲基治疗增强ATP的产生，挽救了Sigma-1R（E102Q）过表达引起的线粒体损伤。综上所述，在Sigma-1R（E102Q）过表达细胞中观察到的表型表明，丙酮酸甲基补充ATP是治疗由Sigma-1R突变引起的ALS的潜在治疗策略。

项目成果

パーキンソン病モデル動物における nobiletin による学習・認知改善作用のメカニズム

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• 发表时间: 2013
• 作者: 矢吹 悌;大泉 康;福永 浩司
• 通讯作者: 福永 浩司

Impact of sigma-1 receptor in cardiovascular and neurodegenerative diseases

sigma-1 受体对心血管和神经退行性疾病的影响

• 发表时间: 2013
• 作者: 小野里美咲;塩田倫史;矢吹悌;大和田祐二;福永浩司;Uchida Y;Kohji Fukunaga;福永浩司;Omi M;Kohji Fukunaga
• 通讯作者: Kohji Fukunaga

Synergic induction of cardiac hypertrophy by CaMKII and calcineurin activities

CaMKII 和钙调神经磷酸酶活性协同诱导心脏肥大

• 发表时间: 2013
• 作者: Norifumi Shioda;Yuji Owada and Kohji Fukunaga;Nakatochi M;Kohji Fukunaga
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Oral glutathione administration improves memory deficits following transient brain ischemia

口服谷胱甘肽可改善短暂性脑缺血后的记忆缺陷

• 发表时间: 2014
• 作者: Hideaki Tagashira;Takayuki Matsumoto;Kumiko Taguchi;Tsuneo Kobayashi and Kohji Fukunaga;Yasushi Yabuki and Kohji Fukunaga
• 通讯作者: Yasushi Yabuki and Kohji Fukunaga

The molecular mechanisms of neurodegeneration caused by ALS-related sigma-1 receptor mutation

ALS相关sigma-1受体突变引起神经退行性变的分子机制

• 发表时间: 2014
• 作者: Hideaki Tagashira;Yasushi Yabuki;Norifumi Shioda and Kohji Fukunaga
• 通讯作者: Norifumi Shioda and Kohji Fukunaga