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

Abstract

N6-methyladenosine (m6A) is the most prevalent internal RNA modification in eukaryotic transcripts, and YTH structural domain family (YTHDF) 2 is a principal m6A reader that governs RNA stability and turnover. Accumulating evidence indicates that YTHDF2 exerts context-dependent and sometimes opposing functions across major neurological disorders, including Alzheimer’s disease, Parkinson’s disease, glioblastoma, epilepsy, and experimentally induced cognitive and neuropsychiatric conditions. By selectively promoting decay of m6A-marked transcripts - such as leucine rich repeat and immunoglobulin domain containing 2, axis inhibition protein 1, breast cancer type 1 susceptibility protein associated protein 1, mitogen-activated protein kinase kinase 4, family with sequence similarity 134 member B, and NOD-like receptor family pyrin domain-containing 3 - YTHDF2 modulates diverse processes including amyloid processing, Wnt signaling, ferroptosis, neuroinflammation, metabolic homeostasis, and autophagy. Its activity is further shaped by upstream regulatory pathways (e.g., epidermal growth factor receptor-SRC proto-oncogene, non-receptor tyrosine kinase-extracellular signal-regulated kinase and protein arginine methyltransferase 6-cyclin-dependent kinase 9) and by dynamic interplay with m6A writers and erasers, including methyltransferase like 14 and fat mass and obesity-associated protein. This mini-review synthesizes recent mechanistic advances, emphasizes regional and cell-type heterogeneity of YTHDF2 function, and proposes a “dose-target dependency” framework to reconcile its bidirectional effects. We also outline emerging translational strategies aimed at evaluating YTHDF2 as a mechanistic biomarker and a selectively tractable therapeutic target in neurological disease.

Keywords: YTH structural domain family protein 2; N6-methyladenosine; Alzheimer’s disease; Parkinson’s disease; Glioblastoma

Core Tip: This mini-review synthesizes evidence that the N6-methyladenosine (m6A) reader YTH structural domain family (YTHDF) 2 exerts context-dependent, often bidirectional effects in neurodegeneration and glioma by directing degradation of m6A-marked transcripts. YTHDF2 is regulated by upstream axes and interacts functionally with m6A writers/erasers. Because its net effect depends on cell type, brain region, disease stage and target dosage, YTHDF2 constitutes both a mechanistic biomarker and a selectively tractable therapeutic target; advancing translation will require cell/region-resolved targetome mapping, longitudinal dynamics, and testing of conditional genetics, small molecules and antisense oligonucleotides.