P-53

The IRE1/XBP1 signaling pathway is the most conserved component of the endoplasmic reticulum unfolded protein response (UPR^ER). Activating this branch to correct defects in ER proteostasis is regarded as a promising anti-Parkinson's disease (PD) strategy. P-53 is a marine-derived xyloketal B analog which exhibited potential neuroprotective activities in previous research studies; however, the molecular mechanism underneath its protective effect remains unknown. Herein, a transcriptomic approach was introduced to explore the protective mechanism of P-53. RNA microarray profiling was conducted based on an MPP⁺-induced C. elegans PD model, and bioinformatics analyses including GO enrichment and PPI network analysis were subsequently performed. In particular, the recovery of the impaired UPR^ER was highlighted as a main physiological change caused by P-53, and a cluster of genes including abu and hsp family genes which are involved in the IRE1/XBP1 branch of the UPR^ER were identified as the key genes related to its neuroprotective effect. The transcription levels of these key genes were validated by RT-qPCR assays. Further results showed that P-53 enhanced the phosphorylation of IRE1, the splicing of xbp-1 mRNA, and the translation of XBP1S and boosted the expression level of the downstream targets of the IRE1/XBP1 signaling pathway. Moreover, it was also demonstrated that P-53 accelerated the scavenging of misfolded α-synuclein and attenuated the correlative mitochondrial dysfunction. Finally, the protective effect of P-53 against MPP⁺-induced dopaminergic neuronal loss was assessed. Taken together, these results revealed that P-53 plays its neuroprotective role through regulating of the IRE1/XBP1 signaling pathway and laid the foundation for its further development as an ER proteostasis-regulating agent.