Regulatory Mechanisms of the RNA Modification m(6)A and Significance in Brain Function in Health and Disease

RNA modifications have emerged as an additional layer of regulatory complexity governing the function of almost all species of RNA. N(6)-methyladenosine (m(6)A), the addition of methyl groups to adenine residues, is the most abundant and well understood RNA modification. The current review discusses the regulatory mechanisms governing m(6)A, how this influences neuronal development and function and how aberrant m(6)A signaling may contribute to neurological disease. M(6)A is known to regulate the stability of mRNA, the processing of microRNAs and function/processing of tRNAs among other roles. The development of antibodies against m(6)A has facilitated the application of next generation sequencing to profile methylated RNAs in both health and disease contexts, revealing the extent of this transcriptomic modification. The mechanisms by which m(6)A is deposited, processed, and potentially removed are increasingly understood. Writer enzymes include METTL3 and METTL14 while YTHDC1 and YTHDF1 are key reader proteins, which recognize and bind the m(6)A mark. Finally, FTO and ALKBH5 have been identified as potential erasers of m(6)A, although there in vivo activity and the dynamic nature of this modification requires further study. M(6)A is enriched in the brain and has emerged as a key regulator of neuronal activity and function in processes including neurodevelopment, learning and memory, synaptic plasticity, and the stress response. Changes to m(6)A have recently been linked with Schizophrenia and Alzheimer disease. Elucidating the functional consequences of m(6)A changes in these and other brain diseases may lead to novel insight into disease pathomechanisms, molecular biomarkers and novel therapeutic targets.