Dynamic m6A Methylation in Neurodevelopmental and Neurodegenerative Disorders

Abstract

N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic RNA, has emerged as a key epitranscriptomic regulator in the central nervous system, coordinating gene expression programs that govern neural development, synaptic plasticity, and neuronal adaptation throughout the lifespan. This review synthesizes emerging evidence that m6A dysregulation represents a shared epitranscriptomic mechanism linking neurodevelopmental and neurodegenerative disorders, highlighting a mechanistic convergence that bridges these traditionally distinct disease categories. Dysregulation of m6A-mediated control of neurogenesis, synaptic maturation, and dopaminergic development has been implicated in neurodevelopmental disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, and intellectual disability. In neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, m6A dysregulation mediates multiple interconnected pathogenic processes, including neuroinflammation, mitochondrial dysfunction, tau hyperphosphorylation and aggregation, α-synuclein dysregulation, and impaired neuronal repair. Environmental stressors and metabolic perturbations modulate m6A modification patterns, suggesting that gene–environment interactions contribute to disease susceptibility through epitranscriptomic mechanisms. m6A modification functions as a dynamic molecular switch governing neural plasticity and circuit function across early development, adulthood, and aging, and its dysregulation predisposes individuals to neurological disease manifestation throughout the lifespan. Advances in cell-type-specific and circuit-resolved m6A profiling will deepen our understanding of m6A dysregulation and strengthen its translational potential as both a diagnostic biomarker and a therapeutic target in neurological diseases. Furthermore, we evaluate pharmacological and molecular strategies targeting m6A regulatory machinery, including the writers METTL3/METTL14, the erasers FTO/ALKBH5, and reader proteins, as promising therapeutic approaches to restore aberrant neuronal circuit function in neurodevelopmental and neurodegenerative disorders.