ALDH2 protects against dopaminergic neuronal cell ferroptosis by enhancing the enzyme activity of PRDX6 in Parkinson’s disease

Emerging evidence suggests that ferroptosis is probably involved in the selective loss of dopaminergic neurons in Parkinson's disease (PD). Acetaldehyde dehydrogenase 2 (ALDH2) plays an important role in detoxifying lipid aldehydes derived from lipid peroxidation, a process that is closely linked to ferroptosis. In our study, ALDH2 knockout (KO) mice were more susceptible to the loss of tyrosine hydroxylase-positive neurons and behavioral changes in a PD mouse model. Similar observations were made in a knock-in (KI) mouse model with one of the most common single-nucleotide polymorphisms of ALDH2, rs671. Interestingly, ALDH2 KO or KI mice showed enhanced ferroptosis in the SN. Moreover, expression of ALDH2 modified the sensitivity of SH-SY5Y cells to ferroptosis inducers. Mechanistic studies have shown that ALDH2 regulates neuronal cell ferroptosis by interacting with the antioxidant enzyme peroxiredoxin 6 (PRDX6) to enhance its enzymatic activity, whereas the ALDH2 rs671 variant weakens its binding to PRDX6.