Neuromodulatory role and therapeutic potential of N 6 -methyladenosine RNA methylation in neurodegenerative diseases.

N 6 -methyladenosine RNA methylation, an essential post-transcriptional modification, dynamically regulates RNA metabolism and plays a crucial role in neuronal function. Growing evidence suggests that dysregulated N 6 -methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis. However, the precise mechanisms by which N 6 -methyladenosine modification influences these conditions remain unclear. This review summarizes the role of m 6 A modification and its associated regulators in neurodegeneration, focusing on their involvement in key pathological processes. In Alzheimer's disease, m 6 A modification contributes to synaptic dysfunction, mitochondrial damage, and neuronal apoptosis. Evidence from APP/PS1, 5xFAD, tau transgenic, and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesity-associated protein influence Alzheimer's disease progression through neuroinflammation, circular RNAs dysregulation, and autophagy-related mechanisms. In Parkinson's disease, altered N 6 -methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs. In multiple sclerosis and amyotrophic lateral sclerosis, N 6 -methyladenosine affects immune activation, myelin repair, and the regulation of disease-associated genes such as TDP-43 . Beyond N 6 -methyladenosine, other RNA methylation modifications-such as m 1 A, m 5 C, m 7 G, uracil, and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function, RNA metabolism, and neuronal stress responses. Additionally, N 6 -methyladenosine exhibits cell type-specific functions: in microglia, it regulates inflammatory activation and phagocytic function; in astrocytes, it modulates metabolic homeostasis and glutamate-associated neurotoxicity; in neurons, it affects synaptic function and neurodegeneration-related gene expression; and in adult neural stem cells, it controls differentiation, neurogenesis, and cognitive plasticity. Recently, several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesity-associated protein have been developed to modulate N 6 -methyladenosine modification, providing new opportunities for disease intervention, with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy. However, challenges persist in optimizing the specificity and delivery of these therapeutic approaches.