Double-edged role of N6-methyladenosine reader YTH structural domain family protein 2 in neurological disorders: Molecular mechanisms and translational prospects

Figure 1 Context-dependent and bidirectional roles of the N6-methyladenosine reader YTH structural domain family protein 2 across central nervous system-associated disorders. This schematic illustrates how YTH structural domain family (YTHDF) 2 integrates upstream regulatory inputs, including N6-methyladenosine writers/erasers, signaling pathways, and circadian mechanisms, to selectively promote decay of N6-methyladenosine-marked mRNAs. Depending on disease context, cell type, and target dosage, YTHDF2 regulates distinct downstream pathways across Alzheimer’s disease, Parkinson’s disease, glioblastoma, epilepsy, and amyotrophic lateral sclerosis-related models, resulting in either pathogenic or protective outcomes. The figure highlights a dose-target dependency framework, in which the balance between vulnerable and protective mRNA targets determines the net biological impact of YTHDF2 in central nervous system disorders. YTHDF2: YTH structural domain family protein 2; EGFR: Epidermal growth factor receptor; SRC: SRC proto-oncogene, non-receptor tyrosine kinase; ERK: Extracellular signal-regulated kinase; PRMT6: Protein arginine methyltransferase 6; CDK9: Cyclin dependent kinase 9; METTL14: Methyltransferase like 14; FTO: Fat mass and obesity-associated protein; BMAL1: Brain and muscle ARNT-Like 1; m6A: N6-methyladenosine; LINGO2: Leucine rich repeat and immunoglobulin domain containing 2; APP: Amyloid precursor protein; BACE1: Beta-secretase 1; AXIN1: Axis inhibition protein 1; BAP1: Breast cancer type 1 susceptibility protein associated protein-1; SLC7A11: Solute carrier family 7 member 11; APC: Adenomatous polyposis coli; GSK3β: Glycogen synthase kinase 3 beta; LXRA: Liver X receptor alpha; HIVEP2: Human immunodeficiency virus type I enhancer binding protein 2; FAM134B: Family with sequence similarity 134 member B; ER: Endoplasmic reticulum; Nrf2: Nuclear factor erythroid-2-related factor 2; NR4A2: Nuclear receptor subfamily 4 group a member 2; TDP-43: TAR DNA-binding protein 43; ALS: Amyotrophic lateral sclerosis.