NSUN2-Mediated RNA 5-Methylcytosine Modification of PTEN Regulates Cognitive Impairments of Mice with Sleep Deprivation and Autophagy Through PI3K/AKT Signaling.

Sleep deprivation (SD) impairs learning and memory. Investigating the role of epigenetic modifications, such as 5-methylcytosine (mC), in SD is crucial. This study established an SD mouse model and assessed the mRNA levels of mC-related genes in brain tissue to identify potential candidates. Results indicated a significant elevation of NSUN2 in the SD group. Behavioral assessments using the Morris water maze test revealed cognitive impairments. Notably, inhibiting NSUN2 markedly alleviated these cognitive deficits and reduced autophagy in SD mice. Mechanistically, NSUN2 inhibition led to a pronounced decrease in PTEN levels, and the mC modification of PTEN, which was increased by SD, was significantly reduced following NSUN2 knockdown. It was found that NSUN2 stabilizes PTEN mRNA through methylation. In the SD group, PTEN protein levels were elevated, and this increase was counteracted by NSUN2 inhibition. Collectively, the upregulation of PTEN may diminish the beneficial effects of NSUN2 inhibition on cognitive function and autophagy in SD mice. This study suggests that targeting NSUN2 and PTEN could be a novel therapeutic approach to ameliorate cognitive impairments and autophagy associated with SD, offering a promising strategy for the clinical management of SD-related cognitive deficits.