Involvement of the autophagic pathway in the progression of AMD-like retinopathy in senescence-accelerated OXYS rats.

Abstract

Age-related macular degeneration (AMD) is a complex neurodegenerative disease resulting in a loss of central vision in the elderly. It is currently assumed that impairment of autophagy may be one of the key mechanisms leading to AMD. Here we estimated the influence of age-related autophagy alterations in the retina on the development of AMD-like retinopathy in senescence-accelerated OXYS rats. Significant changes in the expression of the autophagy proteins were absent at the age preceding the development of retinopathy (age 20days). We found increased levels of LC3A/B, Atg7, and Atg12-Atg5 conjugated proteins in the OXYS retina during manifestation of this retinopathy at the age of 3months. By contrast, in the retina of 18-month-old OXYS rats with a progressive stage of retinopathy, we revealed significantly decreased protein levels of Atg7 and Atg12-Atg5 as compared to age-matched Wistar rats. Simultaneously with perturbation of the autophagic response, the necrosome subunits Ripk1 and Ripk3 were detected in the OXYS retina. The downregulation of autophagy markers coincided with amyloid β accumulation (Moab-2) in the retinal pigment epithelium and choroid. Using high-throughput RNA sequencing, we found a missense single-nucleotide polymorphism (SNP) in the Pik3c2b gene associated with autophagy regulation. This SNP was predicted to significantly affect protein structure. Our data prove participation of the autophagic pathway in the progression of AMD-like retinopathy.