Deficiency of aldehyde dehydrogenase 2 sensitizes cells to glutamate-induced cytotoxicity via elevation of GluN1 expression

Glutamate is the principal excitatory neurotransmitter in the central nervous system. It is essential for neurotransmission and synaptic plasticity; however, excessive glutamate leads to neuronal toxicity, which is considered as a key mechanism contributing to neurodegeneration. Aldehyde dehydrogenase 2 (ALDH2) is a key enzyme in ethanol metabolism, which converts the toxic alcohol metabolite acetaldehyde to acetate; meanwhile, ALDH2 is also important for the detoxification of Other reactive aldehydes such as lipid peroxidation product 4-hydroxy-2-nonenal. ALDH2 deficiency has been associated with the acceleration of neurodegeneration and cognitive impairment accompanied by increased brain oxidative damages. However, there is a lack of reports on how ALDH2 deficiency affects glutamate-induced cytotoxicity. In the present study, it was found that ALDH2-deficient N2a cells exhibited heightened susceptibility to glutamate, displaying aggravated oxidative stress, mitochondrial dysfunction, and calcium imbalance in response to glutamate. ALDH2 deficiency led to reduced antioxidant capacity and elevated intracellular calcium concentration at basal state, thus predisposing the cells to a higher sensitivity to glutamate. Further analyses showed that ALDH2 deficiency elevated the expression of GluN1 subunit of N-methyl-D-aspartate receptors (NMDARs), which are major ionic glutamate receptors allowing the passage of calcium. Consistently, treatment with the NMDAR channel blocker MK-801 (100 μM) or knockdown of GluN1 reduced the susceptibility of ALDH2^-/- cells to glutamate, suggesting that the elevation of GluN1 was a key determinant for the increased sensitivity of ALDH2-deficient cells to glutamate-induced cytotoxicity. The results demonstrated that ALDH2 plays a critical protective role in glutamate-induced neuronal cytotoxicity, while blocking the overactivation of NMDARs might be beneficial for preventing glutamate-induced neuronal toxicity in individuals with defective ALDH2.

ALDH2; Calcium influx; Cytotoxicity; GluN1; Glutamate; Reactive oxygen species.