Signal transduction of neuronal survival and death : cross talk

神经元生存和死亡的信号转导：串扰

基本信息

批准号：
13670637
负责人：
MUTOH Tatsuro
金额：
$ 2.37万
依托单位：
Fujita Health University (2002-2003)福井医科大学 (2001)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

In many neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease, abnormal proteins such as Abeta peptides, hyperphosphrylated tau and synuclein are accumulated In the Intra-and extra-cellular spaces of the neurons. Some of them are due to the overload to ERAD system which Initiates the signal for cell death. In this study, we explored the significance of the membrane caveolae or lipid rafts to compete with such signals for cell death acting as a machinery for the protection of the cell death. For these purposes, we initiated to work on the molecular effect of GM1 ganglioside (GM1), main constituent of lipid rafts on the lipid rafts-resident Trk high affinity neurotrophic receptors. Then, we examined the effect of cholesterol depletion with HMG-CoA reductase inhibitor (HCRI) on the Integrity of lipid rafts and the fate of the muscle-derived cell culture system. Finally, we examined the effects of the mutation of presenilin-1 gene, a causative gene for familial Alzheimer's disease on glycosphingolipids biosynthesis and metabolism.These analyses revealed following facts ; 1) Trk was no more reactive to its ligand when GM1 is depleted in the lipid rafts, wheras 2)stable transfection of GMI synthase gene rescued the responsiveness of the Trk protein to its ligand. In L myoblasts, 3)cellular cholesterol depletion with HCRI resulted in the apoptotic cell death provoking the tyrosine phosphorylation of p110 catalytic subunit of phosphatidylinositol-3 kinase. 4) In these conditions, we could no more detect lipid rafts fraction of these cells. In the final, we found that 5) mutation of PSi gene resulted in the prevention of cellular gangliosides and 6)an abnormal subcellular distribution of Trk neurotrophin receptor. These abnormal reduction of cellular gangliosides seemed to be an abnormal reduction of glucosylceramide in the cells.

在许多神经退行性疾病（例如阿尔茨海默病和帕金森病）中，异常蛋白质（例如 Abeta 肽、过度磷酸化的 tau 蛋白和突触核蛋白）积聚在神经元的细胞内和细胞外空间中。其中一些是由于 ERAD 系统过载而引发细胞死亡信号。在这项研究中，我们探讨了膜小窝或脂筏与细胞死亡信号竞争作为保护细胞死亡的机制的重要性。为此，我们开始研究 GM1 神经节苷脂 (GM1)（脂筏的主要成分）对脂筏驻留 Trk 高亲和力神经营养受体的分子效应。然后，我们检查了 HMG-CoA 还原酶抑制剂 (HCRI) 消耗胆固醇对脂筏完整性和肌肉来源细胞培养系统命运的影响。最后，我们检查了家族性阿尔茨海默病的致病基因早老素-1 基因的突变对鞘糖脂生物合成和代谢的影响。这些分析揭示了以下事实： 1) 当脂筏中的 GM1 耗尽时，Trk 不再与其配体发生反应，而 2) GMI 合酶基因的稳定转染挽救了 Trk 蛋白对其配体的反应性。在 L 成肌细胞中，3) HCRI 消耗细胞胆固醇会导致细胞凋亡，从而引发磷脂酰肌醇 3 激酶 p110 催化亚基的酪氨酸磷酸化。 4）在这些条件下，我们无法再检测到这些细胞的脂筏部分。最后，我们发现5）PSi基因突变导致细胞神经节苷脂的抑制和6）Trk神经营养蛋白受体亚细胞分布异常。这些细胞神经节苷脂的异常减少似乎是细胞中葡萄糖神经酰胺的异常减少。