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The analysis of onset of familial amyotrophic lateral sclerosis(FALS) with His46Arg point mutation

His46Arg点突变家族性肌萎缩侧索硬化症（FALS）发病分析

基本信息

批准号：
15590899
负责人：
YAMAGUCHI Tadatoshi
金额：
$ 2.11万
依托单位：
University of Miyazaki (2004)宮崎医科大学 (2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

The correlation between neurological disorders and dehydropyrazines(DHPs) that sugar-derived product having the activity of DNA fragmentation was examined. The damage of SOD function bring the existence of many free copper ion, and the effects of DHPs were accelerated in the cells in anterior horn of spinal cord of FALS patient with His46Arg point mutation, thus cells in central nerve seemed to be impaired. To demonstrate this hypothesis, the affect on the cellular functions of DHPs was analyzed using nerve cell lines.The fluctuation of functional molecules in neural cell ; PC12 and Schwann cell, was assayed. Among three DHPs with different DNA fragmentation activity, DHP with the highest fragmentation activity (Yl-3) markedly affect the cellular function. The expression of structural proteins in the cells was almost unchanged, but beta-catenin expression was decreased in Schwann cells treated wjth Yl-3. Though the morphological changes by the addition of DHPs might indicate apoptosis … More occurred, the fragmentation of apoptosis marker molecule PARP was not detected.The cellular effect was not detected in the presence of low density of DHP and copper ion, independently. MAPK molecules (ERK1/2,JNK, and p38) activate in Schwann cells with coexistence of DHP and copper ion. This suggested that low density DHP could degenerate neural cells with the presence of copper ion in vivo. Among cell cycle regulation systems, the expression of p27 and p16 was decreased and cdc2 protein was inactivated. The cell cycle of DHP-treated cells might indicate the convergence into the G1/S state, and it postulated that mitosis process was inhibited.These results suggested that DHPs influenced MAPK activities with the presence of copper ion, and elevated the probability of onset of neurological disorder.On the other hand, the reaction of DHPs with Cu2+ demonstrated that the presence of Cu2+ accelerated the effect of DHPs in the reaction system. A part of the results already was in press (Biol.Pharm.Bull.,2005), and other was submitted and then be under examination. Less

研究了具有DNA断裂活性的糖衍生物脱氢吡嗪类药物（DHPs）与神经系统疾病的关系。His 46 Arg点突变的患者脊髓前角细胞SOD功能受损，导致大量游离铜离子的存在，DHP的作用增强，中枢神经细胞受损。为了证明这一假说，我们用神经细胞系分析了DHP对细胞功能的影响，并测定了神经细胞PC 12和雪旺细胞中功能分子的波动。在三种不同DNA断裂活性的DHP中，断裂活性最高的DHP（Y1 -3）对细胞功能有显著影响。细胞中结构蛋白的表达几乎没有变化，但用Yl-3处理的许旺细胞中β-连环蛋白的表达减少。虽然加入DHP后的形态学变化可能表明细胞凋亡 ...更多信息在低浓度DHP和铜离子单独存在时，未检测到细胞效应。MAPK分子（ERK 1/2、JNK和p38）在DHP和铜离子共存的雪旺细胞中活化。提示低浓度DHP可使体内铜离子存在下的神经细胞发生变性。在细胞周期调控系统中，p27和p16表达降低，cdc 2蛋白失活。DHP处理的细胞周期可能表明细胞进入G1/S期，有丝分裂过程受到抑制，这些结果表明DHP在铜离子存在下影响MAPK活性，增加神经系统疾病发生的可能性。DHP与Cu ~（2+）的反应表明，Cu ~（2+）的存在加速了DHP在反应体系中的作用。部分结果已经出版（Biol.Pharm. Bull.，2005年），其他已提交，然后正在审查。少