The role and regulatory mechanism of m6A methylation in the nervous system

Abstract

N6-methyladenosine (m⁶A) modification regulates RNA translation, splicing, transport, localization, and stability at the post-transcriptional level. The m⁶A modification has been reported to have a wide range of effects on the nervous system, including neurogenesis, cerebellar development, learning, cognition, and memory, as well as the occurrence and development of neurological disorders. In this review, we aim to summarize the findings on the role and regulatory mechanism of m⁶A modification in the nervous system, to reveal the molecular mechanisms of neurodevelopmental processes, and to promote targeted therapy for nervous system-related diseases.

Keywords: development; m6A methylation; mechanism; nervous system; neurological disorders.

FIGURE 1

The molecular mechanism of RNA m⁶A modification. m⁶A methylation was catalyzed by the writer complex, including METTL3, METTL14, METTL16, WTAP, KIAA1429, RBM15/15B, and ZC3H13. The m⁶A modification was erased by demethylases, including FTO and ALKBH5. The m⁶A-modified RNA reader proteins included YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, HNRNPC/G, HNRNPA2B1, Prrc2A, and eIF3.

FIGURE 2

m⁶A modification dysfunction related diseases in the central nervous system. Abbreviations: AD (Alzheimer’s disease), PD (Parkinson’s disease), GBM (Glioblastoma), MDD (Major depressive disorder), Aβ (amyloid-β), Tau (Tau protein), mTOR (Mammalian target of rapamycin signaling pathway), Ephrin-B2 (erythropoietin-producing hepatocyte receptor-interacting-B2), MGMT (O⁶-methylguanine-DNA methyltransferase), APNG (alkylpurine-DNA-N-glycosylase), SRSF7 (Serine/arginine-rich splicing factor 7), pri-miR-10a (primary microRNA-10a), FOXM1 (transcription factor FOXM1), HK2 (Hexokinase 2), ADRB2 (Adrenoceptor beta 2), CaMKII (Calcium-calmodulin-dependent protein kinase II), CREB (cAMP response element-binding protein), miR-335 (microRNA-335), miR-421-3P (microRNA-421-3p).