Common Non‐East Asian Aldehyde Dehydrogenase 2 Deficiencies; Potential Drug Target for Alzheimer's Disease and Mitochondrial Dysfunction

Abstract

Aldehyde dehydrogenase 2 (ALDH2) catalyzes the oxidation and detoxification of aliphatic aldehydes, including acetaldehyde. About 40% of East Asians carry a single point mutation in ALDH2*2 (E504K) that contributes to a severe enzyme deficiency and accumulation of toxic reactive aldehydes. We previously identified Alda‐1 (an aldehyde dehydrogenase activator) that reduces aldehydic load by increasing the catalytic activity and stability of wild type enzyme and by correcting the structural defect in ALDH2*2, in vitro and in vivo. Using the ExAC genomic database, we identified and characterized new ALDH2 variants in several non‐East Asian populations. Nine other ALDH2 variants with a single point mutation were identified among Latino, African, and Finnish ethnic groups at a frequency of >1/1000. We focused on three variants, two with a reported frequency of 2.5% and one with a reported frequency of 1.2%. All three newly‐identified ALDH2 mutants exhibited a significant reduction in activity as compared with wild type enzyme (ALDH2*1/*1; WT) but differed in their sensitivity to Alda‐1‐induced activation as determined in vitro and in 3T3 cells overexpressing each of the variants. Acetaldehyde‐induced toxicity (mitochondrial dysfunction and cell death) was also higher in these cells relative to 3T3 cells overexpressing WT ALDH2. Recent evidence suggests a correlation between increased aldehydic load and Alzheimer's disease. In line with this evidence, there was a greater mitochondrial dysfunction and cell toxicity induced by oligomeric amyloid beta1‐42 (oAb1‐42) in 3T3 cells expressing inactive variants of ALDH2 relative to WT enzyme. These defects were reduced by Alda‐1 co‐treatment. Ethanol, which is consumed by ~80% of the world's population, increases aldehydic load. Using ALDH2*2 knockin mice, we found that chronic exposure to ethanol (1g/kg/day) for 11 weeks increased oxidative stress, apoptosis, and Ab1‐42 accumulation in their brains relative to WT mice. Co‐treatment with Alda‐1 (10mg/kg/day) significantly reduced these toxic effects in both WT and ALDH2*2 mice. Finally, treatment of Alzheimer's disease patient‐derived fibroblasts with 0.1% ethanol resulted in a higher mitochondrial dysfunction and cytotoxicity relative to fibroblasts of healthy subjects. These effects were reduced by co‐treatment with Alda‐1, even in cells overexpressing ALDH2*2.In conclusion, ALDH2 deficiencies are much more common than previously thought, possibly affecting >10% of people worldwide. As aldehydic load contributes to many chronic diseases, including Alzheimer's disease, drugs that activate ALDH2 and correct the functional deficiency may provide benefit to those at risk.Support or Funding InformationSupported by NIAAA11147 R37 Merit award to DM‐RThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.