Signal transduction of neuronal survival and death : cross talk

在许多神经退行性疾病如阿尔茨海默病和帕金森病中，异常蛋白质如Abeta肽、过度磷酸化的tau和突触核蛋白在神经元的细胞内和细胞外空间中积累。它们中的一些是由于ERAD系统的过载，ERAD系统启动了细胞死亡的信号。在这项研究中，我们探讨了膜小窝或脂筏的意义，以竞争这些信号细胞死亡作为一种机制，为细胞死亡的保护。为此，我们开始研究脂筏的主要成分神经节苷脂GM 1对脂筏上的Trk高亲和力神经营养受体的分子作用。然后，我们研究了用HMG-CoA还原酶抑制剂（HCRI）去除胆固醇对脂筏完整性和肌源性细胞培养系统命运的影响。最后，我们研究了家族性阿尔茨海默病的致病基因早老素-1基因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GM 1耗尽时，Trk对其配体不再具有反应性，而2）稳定转染GMI合酶基因拯救了Trk蛋白对其配体的反应性。在L成肌细胞中，3）HCRI消耗细胞胆固醇导致细胞凋亡，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，我们不能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减少和6）Trk神经营养因子受体亚细胞分布的异常。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。

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.