N6-methyladenosine methylation: a novel key to unlocking mental disorders

Abstract

More than 100 types of RNA modifications have been identified in mammalian cells, among which N6-methyladenosine (m6A) is the most prevalent. This reversible and dynamic modification involves methyltransferases, demethylases, and reader proteins. Aberrant expression of m6A-related regulatory proteins in the nervous system significantly impacts neuronal physiology, contributing to mental disorders such as depression, autism spectrum disorder, and schizophrenia. This review summarizes the role of m6A methylation in the pathogenesis of mental disorders and highlights its potential as a biomarker and therapeutic target, providing a comprehensive reference for future research and clinical interventions.

Keywords: learning and memory; m6A methylation; mental disorders; substance addiction.

Figure 1

Overview of the m6A RNA modification machinery. N6-methyladenosine (m6A) methylation is catalyzed by a multi-component writer complex comprising METTL3, METTL14, METTL16, WTAP, VIRMA (KIAA1429), RBM15/15B, and ZC3H13. These methyltransferases install m6A modifications on mRNA bases. The modification can be reversed by eraser enzymes such as FTO and ALKBH5, which mediate m6A demethylation. Reader proteins, including YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, FMRP, PRRC2A, ELAVL1, eIF3, and HNRNPC/A2B1, recognize and bind to m6A-modified RNA to regulate various post-transcriptional processes, such as mRNA translation, degradation, and microRNA processing.