Regulatory Mechanisms of the RNA Modification m ⁶A 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 ⁶A), 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 ⁶A, how this influences neuronal development and function and how aberrant m ⁶A signaling may contribute to neurological disease. M ⁶A 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 ⁶A 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 ⁶A 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 ⁶A mark. Finally, FTO and ALKBH5 have been identified as potential erasers of m ⁶A, although there in vivo activity and the dynamic nature of this modification requires further study. M ⁶A 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 ⁶A have recently been linked with Schizophrenia and Alzheimer disease. Elucidating the functional consequences of m ⁶A changes in these and other brain diseases may lead to novel insight into disease pathomechanisms, molecular biomarkers and novel therapeutic targets.