Nsun5 deficiency leads to impaired myelin integrity and sleep disruption

Sleep disruption is common in disorders involving white-matter abnormalities, but the molecular pathways linking ribosomal RNA modification to disordered sleep remain unclear. NSUN5, which encodes an rRNA methyltransferase, is deleted in most patients with Williams-Beuren syndrome (WBS), a condition frequently accompanied by sleep problems. This clinical association suggests that loss of NSUN5 may contribute to sleep dysfunction, potentially through mechanisms relevant to white-matter integrity and neural activity. We combined electroencephalography/electromyography phenotyping, transcriptomics, ribosome profiling, nascent proteomics, proteomics, electron microscopy, positron emission tomography-computed tomography, and pharmacological rescue experiments in Nsun5 -knockout mice to define how loss of Nsun5-dependent 28 S ribosomal RNA 5-methylcytosine affects white-matter integrity and sleep. Nsun5 deficiency markedly reduced 28 S rRNA m 5 C levels and led to selective translational dysregulation rather than global translational failure. The affected translational programs were enriched in myelination-related pathways and voltage-gated potassium channel subunits, including Kcna1 and Kcna2. At the cellular and tissue levels, these alterations were associated with oligodendrocyte loss, diffuse hypomyelination of the corpus callosum, and increased regional cortical metabolic activity. Correspondingly, Nsun5 -knockout mice exhibited reduced non-rapid-eye-movement sleep and altered nocturnal sleep organization. Treatment with clemastine significantly improved sleep abnormalities and restored myelin integrity, while treatment with 4-aminopyridine also alleviated the sleep phenotype. These findings suggest that Nsun5-dependent rRNA methylation contributes to sleep disruption in association with white-matter dysfunction and altered potassium-channel-related protein abundance. Our results provide a preclinical framework for understanding sleep disturbances associated with WBS and other myelin-related neurological conditions.