Dataset Information

Proteome profiling of N2a pretreated with ALDH2

ABSTRACT: Aldehyde dehydrogenase 2 family member (ALDH2) is a key mitochondrial dehydrogenase that functions in the detoxification of acetaldehyde, and endogenous 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde generated by polyunsaturated fatty acid peroxidation. In this study, we found that altered ALDH2 enzyme activity regulate the Abeta pathology in neuron. However, the underlying mechanism is unknown. The aim of this study was to reveal the critical proteins expression changes induced by altered ALDH2 activity. After bioinformatic analysis, a total of 3812 proteins were detected in the proteomic datasets. Compared with untreated N2a-APP, daidzin treatment induced lower ALDH2 activity caused down-regulation of 14 proteins and up-regulation of 31 proteins. KEGG pathway analysis indicate altered fatty acid metabolism. ALDH2 agonist Alda-1 treatment did not significantly alter protein expression levels change.

ORGANISM(S): Mus Musculus

SUBMITTER: Wei Ge

PROVIDER: PXD047209 | iProX | Fri Nov 24 00:00:00 GMT 2023

REPOSITORIES: iProX

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Publications

The aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology.

Wang Xia X Wang Jiayu J Chen Yashuang Y Qian Xiaojing X Luo Shiqi S Wang Xue X Ma Chao C Ge Wei W

Nature communications 20240322 1

In the ALDH2 rs671 variant, a guanine changes to an adenine, resulting in a dramatic decrease in the catalytic activity of the enzyme. Population-based data are contradictory about whether this variant increases the risk of Alzheimer's disease. In East Asian populations, the prevalence of the ALDH2 rs671 variant is 30-50%, making the National Human Brain Bank for Development and Function (the largest brain bank in East Asia) an important resource to explore the link between the ALDH2 rs671 polym ...[more]

PMID: 38519490

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Project description:Obesity and type 2 diabetes have reached pandemic proportion. In particular, the population with diabetes is expected to rise rapidly in East and South Asia. ALDH2 (acetaldehyde dehydrogenase 2, mitochondrial) is the key metabolizing enzyme of acetaldehyde and other toxic aldehydes, such as 4-hydroxynonenal (4-HNE). A missense Glu504Lys mutation of the ALDH2 gene is prevalent in 560 million East Asians, resulting in reduced ALDH2 enzymatic activity. We found that Aldh2 knock-in (KI) mice mimicking human Glu504Lys mutation were prone to develop diet-induced obesity, glucose intolerance, insulin resistance, and fatty liver compared with controls due to reduced adaptive thermogenesis and energy expenditure. We found elevated 4-HNE levels and increased 4-HNE adducted proteins due to reduced activity of ALDH2 of the brown adipose tissue (BAT) from the Aldh2 homozygous KI mice. Proteomic analyses of the BAT from the Aldh2 KI mice identified increased 4-HNE-adducted proteins involved in mitochondrial fatty acid oxidation (FAO) and electron transport chain (ETC), leading to markedly decreased FAO and mitochondrial respiration of BAT, which is essential for adaptive thermogenesis and energy expenditure. AD-9308 is a water-soluble prodrug of a potent and highly selective ALDH2 activator AD-5591. In vitro, AD-5591 enhanced both WT and mutant ALDH2 enzymatic activities. AD-9308 allosterically activates ALDH2 mainly by partially blocking the substrate exit tunnel, thereby accelerating the substrate-enzyme collision.4-HNE-adducted proteins, especially those involved in mitochondrial fatty acid beta-oxidation and electron transfer chain of the brown adipose tissue from the Aldh2 knock-in mice, leading to impaired mitochondrial dysfunction brown adipose tissue. In vivo, AD-9308 treatment reduced serum 4-HNE levels, ameliorated diet-induced obesity and fatty liver, and improved glucose homeostasis in both Aldh2 WT and KI mice dose-dependently. Our data highlight the therapeutic potential of reducing toxic aldehyde levels by activating ALDH2 for treating metabolic diseases.

Dataset Information

Proteome profiling of N2a pretreated with ALDH2

Publications

The aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology.

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