Mitochondrial ALDH2 deficiency as an oxidative stress.
Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in ethanol metabolism. It is involved in acetaldehyde detoxification. A polymorphism of the ALDH2 gene is specific to North-East Asians. Sensitivity to ethanol is highly associated with this polymorphism (ALDH2(*)2 allele), which is responsible for a deficiency of ALDH2 activity. We 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 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 the apolipoprotein E4 allele (APOE-epsilon4), which has been confirmed to be a risk factor for LOAD. The ALDH2(*)2 allele more significantly affected frequency and age at onset in patients with APOE-epsilon4 than in those without it. These results indicate that the ALDH2 deficiency is a risk factor for LOAD, acting synergistically with the APOE-epsilon 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 act 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.
Ohta
Shigeo
S
Institute of Development and Aging Sciences, Nippon Medical School, Kosugi, Kawasaki, Kanagawa, 211-8533 Japan. ohta@nms.ac.jp
Ohsawa
Ikuroh
I
Kamino
Kouzin
K
Ando
Fujiko
F
Shimokata
Hiroshi
H
D000444:Aldehyde Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology; D000595:Amino Acid Sequence; D000818:Animals; D053327:Apolipoprotein E4; D001057:Apolipoproteins E / Q000235:genetics; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007564:Japan; D008297:Male; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D018384:Oxidative Stress; D016716:PC12 Cells; D010641:Phenotype; D011110:Polymorphism, Genetic; D051381:Rats; D013481:Superoxides / Q000378:metabolism
D053327:Apolipoprotein E4; D001057:Apolipoproteins E; D013481:Superoxides; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial