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Aldehydes accumulated in mitochondria as risk factors to neurodegenerative diseases

线粒体中积累的醛是神经退行性疾病的危险因素

基本信息

批准号：
12470144
负责人：
OHTA Shigeo
金额：
$ 9.22万
依托单位：
Department of Biochemistry and Cell Biology, Institute of Development and Aging Sciences, Graduate School of Medicine, Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is involved in ethanol metabolism by playing a major role in acetaldehyde detoxification : A polymorphism of the ALDH2 gene is specific to north Asians. Sensitivity to ethanol is highly associated with this polymorphism (ALDH2^*2 allele), which is responsible for a deficiency of ALDH2 activity. We at first show that this deficiency influences the risk for late-onset Alzheimer's disease (LOAD) by a case-control study in a Japanese population. In a comparison of 447 patients with sex, age and region-matched non-demented controls, the genotype frequency for carrying the ALDH2^*2 allele was significantly higher in the patients than in the controls (p=0.001). Next, we examined the combined effect of the ALDH2^*2 and apolipoprotein E 4 allele (APOE-e4), which has been confirmed be a risk factor for LOAD. The ALDH2^*2 allele more significantly affected frequency and onset-age in patients with APOE-e4 than without. These results indicate that the ALDH2 deficiency is a risk factor for LOAD, acting synergistically with the APOE-e allele. Next, to elucidate the molecular mechanism involved, we obtained ALDH2-deficient cell lines by introducing mouse mutant Aldh2 cDNA into PC12 cells. We speculate that ALDH2 may function to oxidize toxic aldehyde derivatives. Then, we found that the ALDH2-deficient transfectants were highly vulnerable to exogenous 4-hydroxy-2-nonenal, an aldehyde derivative generated from peroxidized fatty acids. In addition, the ALDH2-deficient transfectants were sensitive to oxidative insult induced by antimycin A, accompanied by an accumulation of proteins modified with 4-hydroxy-2-nonenal. Mitochondrial ALDH2 functions as a protector against oxidative stress.

线粒体醛脱氢酶2（ALDH 2）通过在乙醛解毒中发挥主要作用而参与乙醇代谢：ALDH 2基因的多态性是北亚人特有的。对乙醇的敏感性与这种多态性（ALDH 2 ^*2等位基因）高度相关，这是导致ALDH 2活性缺乏的原因。我们首先表明，这种缺陷影响晚发性阿尔茨海默病（LOAD）的风险，在日本人口的病例对照研究。将447名患者与性别、年龄和地区匹配的非痴呆对照组进行比较，发现患者携带ALDH 2 ^*2等位基因的基因型频率显著高于对照组（p=0.001）。接下来，我们检测了ALDH 2 ^*2和载脂蛋白E4等位基因（APOE-e4）的联合作用，这已被证实是LOAD的一个危险因素。ALDH 2 ^*2等位基因对APOE-e4患者的发病频率和发病年龄的影响比无APOE-e4患者更显著。这些结果表明，ALDH 2缺乏是LOAD的危险因素，与APOE-e等位基因协同作用。接下来，为了阐明所涉及的分子机制，我们通过将小鼠突变体Aldh 2 cDNA导入PC 12细胞获得了ALDH 2缺陷细胞系。我们推测ALDH 2可能具有氧化有毒醛衍生物的功能。然后，我们发现ALDH 2缺陷的转染子非常容易受到外源性4-羟基-2-壬烯醛的影响，4-羟基-2-壬烯醛是由过氧化脂肪酸产生的醛衍生物。此外，ALDH 2缺陷型转染子对抗霉素A诱导的氧化损伤敏感，伴随着用4-羟基-2-壬烯醛修饰的蛋白质的积累。线粒体ALDH 2作为抗氧化应激的保护剂发挥作用。