Increased m6A modification of BDNF mRNA via FTO promotes neuronal apoptosis following aluminum-induced oxidative stress

N6-methyladenosine (m⁶A) RNA modification is a new epigenetic molecular mechanism involved in various biological or pathological processes. Exposure to aluminum (Al) has been considered to promote neuronal Apoptosis resulting in cognitive dysfunction, yet whether m⁶A modification participates in the underlying mechanism remains largely unknown. Here, rats exposed to aluminum-maltolate [Al(mal)₃] for 90 days showed impaired learning and memory function and elevated Apoptosis, which were related to the increased m⁶A level and decreased fat mass and obesity-associated protein (FTO, an m⁶A demethylase) in the hippocampus. Accordingly, similar results presented in PC12 cells following Al(mal)₃ treatment and FTO overexpression relieved the increased Apoptosis and m⁶A level in vitro. Next, we identified brain-derived neurotrophic factor (BDNF) as the functional downstream target of FTO in a m⁶A-dependent manner. Furthermore, it was found that as the onset of aluminum neurotoxicity, oxidative stress may be the upstream regulator of FTO in aluminum-induced Apoptosis. Taken together, these results suggest that increased m⁶A modification of BDNF mRNA via FTO promotes neuronal Apoptosis following aluminum-induced oxidative stress.

Aluminum; Apoptosis; BDNF; FTO; Oxidative stress; m(6)A modification.