Loss of ribosomal RNA methyltransferase Nsun5 Leads to Hypomyelination and Reduced Sleep Amount

Sleep is regulated by intricate homeostatic and circadian systems and is influenced by genetic, environmental, and lifestyle factors. However, the roles of the epitranscriptome in sleep-wake regulation remain to be clarified. Here, we find that mice lacking the rRNA methyltransferase Nsun5 exhibit prolonged wakefulness. The absence of Nsun5 decreases 28S rRNA m5C levels, impairing the translational efficiency of nascent proteins associated with myelination, microtubule-based movement, and ribosome binding. This leads to a decreased number of oligodendrocytes and hypomyelination. These deficits result in increased excitability, particularly within the cortex. Notably, restoring myelination properties with clemastine or blocking the abnormally exposed voltage-gated potassium channels rescues the sleep phenotype, suggesting that reduced sleep is associated with hypomyelination. These findings highlight the significant role of epigenetic modifications in sleep regulation and offer broad mechanistic and therapeutic implications for brain disorders involving both myelin and sleep disturbances.