TRIM59 attenuates sleep disturbances and improves hippocampal neuronal injury in PCPA-induced sleep-deprived male mice via the NLRP3 signaling pathway.

Although TRIM59 has been reported to exert neuroprotective effects against brain injury, its role and underlying mechanisms in sleep disturbances remain unclear. This study aimed to elucidate the effect of Tripartite Motif Containing 59 (TRIM59) on sleep disorders and the associated hippocampal damage and cognitive dysfunction. Male ICR mice were randomly divided into four groups (n = 10 per group): control group, PCPA group, PCPA + AAV-vector group, and PCPA + AAV-TRIM59 group. A sleep disturbance model was established in male ICR mice by intraperitoneal injection of 300 mg/kg p-chlorophenylalanine (PCPA), and adeno-associated virus encoding TRIM59 (AAV-TRIM59) was stereotactically delivered into the hippocampal region to modulate TRIM59 expression. Sleep latency and duration were assessed through the pentobarbital sodium-induced sleep test. The levels of hippocampal neurotransmitters, including 5-hydroxytryptophan (5-HTP), serotonin (5-HT), γ-aminobutyric acid (GABA), and glutamate (Glu), were quantified using ELISA. Spatial learning and memory were evaluated using the Morris water maze, measuring swimming speed, escape latency, frequency of platform crossings, and duration spent in the target quadrant. Hippocampal histopathology was analyzed by hematoxylin and eosin (H&E) staining, while protein expression of the NLRP3 inflammasome in hippocampal tissue was assessed by Western blot. Statistical analyses were conducted using one-way ANOVA followed by Bonferroni post hoc tests. The results revealed that sleep deprivation significantly reduced TRIM59 expression in the hippocampus. Overexpression of TRIM59 increased 5-HTP, 5-HT and GABA levels, reduced Glu content, shortened sleep latency, and prolonged sleep duration in PCPA-treated mice. Moreover, TRIM59 improved spatial learning and memory by increasing the number of platform crossings and time spent in the target quadrant while decreasing escape latency. TRIM59 also mitigated hippocampal injury by reducing neuronal atrophy and intercellular vacuolation and suppressing the expression of the NLRP3 inflammasome. However, this study has certain limitations, including the lack of long-term evaluation of TRIM59 overexpression and the absence of validation in clinical trials.