Pathogenic mechanism and therapeutic intervention of impaired N⁷-methylguanosine (m⁷G) tRNA modification.

Abstract

Mutations modification enzymes including the tRNA N⁷-methylguanosine (m⁷G) methyltransferase complex component WDR4 were frequently found in patients with neural disorders, while the pathogenic mechanism and therapeutic intervention strategies are poorly explored. In this study, we revealed that patient-derived <i>WDR4</i> mutation leads to temporal and cell-type-specific neural degeneration, and directly causes neural developmental disorders in mice. Mechanistically, <i>WDR4</i> point mutation disrupts the interaction between WDR4 and METTL1 and accelerates METTL1 protein degradation. We further uncovered that impaired tRNA m⁷G modification caused by <i>Wdr4</i> mutation decreases the mRNA translation of genes involved in mTOR pathway, leading to elevated endoplasmic reticulum stress markers, and increases neural cell apoptosis. Importantly, treatment with stress-attenuating drug Tauroursodeoxycholate (TUDCA) significantly decreases neural cell death and improves neural functions of the <i>Wdr4</i> mutated mice. Moreover, adeno-associated virus mediated transduction of wild-type WDR4 restores METTL1 protein level and tRNA m⁷G modification in the mouse brain, and achieves long-lasting therapeutic effect in <i>Wdr4</i> mutated mice. Most importantly, we further demonstrated that both TUDCA treatment and WDR4 restoration significantly improve the survival and functions of human iPSCs-derived neuron stem cells that harbor the patient's <i>WDR4</i> mutation. Overall, our study uncovers molecular insights underlying <i>WDR4</i> mutation in the pathogenesis of neural diseases and develops two promising therapeutic strategies for treatment of neural diseases caused by impaired tRNA modifications.