Neuromodulatory role and therapeutic potential of N6-methyladenosine RNA methylation in neurodegenerative diseases

Abstract

N6-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 N6-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 N6-methyladenosine modification influences these conditions remain unclear. This review summarizes the role of m6A modification and its associated regulators in neurodegeneration, focusing on their involvement in key pathological processes. In Alzheimer's disease, m6A 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 METTL3 and FTO influence Alzheimer's disease progression through neuroinflammation, circRNA dysregulation, and autophagy-related mechanisms. In Parkinson's disease, altered N6-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, N6-methyladenosine affects immune activation, myelin repair, and the regulation of disease-associated genes such as TDP- 43. Beyond N6-methyladenosine, other RNA methylation modifications-such as m1A, m5C, m7G, uracil, and pseudouridine-are implicated in neurodegenerative diseases through their regulation of mitochondrial function, RNA metabolism, and neuronal stress responses. Additionally, N6- 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 METTL3 or FTO have been developed to modulate N6-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.

Keywords: Alzheimer's disease; Parkinson's disease; RNA modification; amyotrophic lateral sclerosis; cell type; methyltransferase-like 3; multiple sclerosis; neurodegeneration; neuroinflammation; therapeutic strategy.