Downregulation of m6A demethylase ALKBH5 promotes AuNP-induced neural stem cell quiescence via regulating ID4 expression

Abstract

Gold nanoparticles (AuNPs) have been widely used in the biomedical field due to their unique physical and chemical properties, and thus pose a potential risk to human health. However, at present, the toxic effects and related mechanisms of AuNPs are still largely unknown; in particular, their long-term neurotoxicity risk has been underestimated. In this study, we found that AuNP treatment induced the quiescence of neural stem cells (NSCs) by upregulating the expression of inhibitors of DNA binding/differentiation proteins 4 (ID4) in a size-effect dependent manner. Further mechanism analysis showed that AuNP treatment enhanced the N6-methyladenosine (m⁶A) modification and thereafter the mRNA stability of ID4 via downregulation of the expression of demethylase ALKBH5, leading to increased ID4 expression in an m⁶A reader IGF2BP3 dependent manner and subsequent NSC quiescence. In summary, our findings demonstrate that m⁶A modification-dependent ID4 upregulation is indispensable for NSC quiescence and neurotoxicity induced by low-dose AuNPs, providing novel insight for recognizing the health risk of AuNPs and a new strategy for preventing AuNP-induced disorder of stem cell development.