The autophagy modulation is conditioned by p53 p.Arg72Pro variant during the retinal neurodegeneration

Abstract

Purpose : Retinal detachment (RD) is defined as the separation of the neuroretina from the pigment epithelium, resulting in a neurodegenerative process characterized by the remodeling of the retina and the death of its neurons. Autophagy, a catabolic pathway mediated by the lysosomal system, has been associated with pathological states of the retina. The clinical evolution of patients is influenced by genetic factors such as p.Arg72Pro p53 polymorphism. In this scenario, we set out to evaluate the influence of the p.Arg72Pro polymorphism of the TP53 gene (rs1042522) on autophagy after retinal detachment.

Methods : A cohort of 180 patients underwent RD surgery. Humanized TP53 Arg72Pro mice were used. Genotyping of the p.Arg72Pro TP53 polymorphism was performed by PCR-RFLP using the restriction enzyme BstU1. The relative gene expression of autophagy-related genes was determined by quantitative real-time PCR (qPCR). The p62 protein was quantified by ELISA. qPCR and ELISA were performed on retinal tissue. Patients underwent a complete ophthalmic examination. Statistical analyses were performed using IBM SPSS Statistics v.25.

Results : Patients carrying the Pro variant showed worse anatomical and functional outcomes after RD surgery compared to patients with the Arg/Arg genotype. Carrying the Pro variant was also associated with higher retinal expression of the autophagy activator BECN1 gene. In addition, p62 protein levels were lower in the retinal tissue of the Pro patients (Figure 1-A). Increased expression of the BECN1, ATG7, and SQSTM1 genes was observed in the retinal tissue of the 72Pro-p53 mice. Finally, the level of p62 protein was lower in the retinal tissue of the 72Pro-p53 mice (Figure 1-B). Our results suggest that autophagy may play a crucial role in retinal neurodegeneration and, thus, in the prognosis of patients after RD.

Conclusions : The human p.Arg72Pro polymorphism in the TP53 gene could play a key role in autophagy modulation in the neurodegenerative process that occurs after RD.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.

 

Figure 1: p62 protein expression. (A) Expression levels of p62 in patients. (B) Expression levels of p62 in mouse model at 3 and 10 days. (*) Significant difference p<0.05.