N6-methyladenosine reader YTHDF1 mediates neuronal apoptosis induced by aluminum via m6A/Bcl-2 manner.

Aluminum (Al) has emerged as a pervasive environmental and industrial risk factor for cognitive impairment and neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Nowadays, N6-methyladenosine (m6A) modification mechanism contributing to aluminum toxicity is gradually gaining attention. m6A modification determines the fate of RNA through m6A "readers". Novel findings indicate that YTH N6-methyladenosine RNA binding protein 1 (YTHDF1, a kind of "readers") participates in various pathological processes induced by some toxic chemicals. Here, we investigated the function of YTHDF1 in neuronal apoptosis induced by aluminum and explored the molecular mechanisms. We first observed the YTHDF1 expression both in vivo and in vitro neuronal apoptosis model induced by aluminum, as well as the reversal effect of YTHDF1 overexpression by lentivirus transfection in vitro. Further, we explored Bcl-2 as a target gene of YTHDF1 and probed their m6A modification manner and molecular mechanism using RIP assay, Me-RIP assay, and Actinomycin D (ActD) assay. Finally, we examined the regulatory role of YTHDF1/m6A/Bcl-2 axis in aluminum neurotoxicity in vitro and in vivo. Functionally, Al(mal)3 treatment decreased YTHDF1 expression, which negatively regulates apoptosis via m6A modification manner. Mechanistically, Bcl-2 acted as the target of YTHDF1, and YTHDF1 regulated Bcl-2 by enhancing its mRNA stability. Collectively, Al(mal)3 treatment inhibited the YTHDF1/m6A/Bcl-2 axis, thereby promoting neuronal apoptosis and subsequent cognitive impairment. This study provides a novel protective strategy against aluminum toxicity.