Alteration of the MEK1/2–ERK1/2 signaling pathway in the retina with age and with the development of amd-like retinopathy

Abstract

Age-related macular degeneration (AMD) is a complex neurodegenerative disease that is a major cause of irreversible visual impairment in developed countries. Although age is the greatest risk factor for AMD, molecular explanations of this clinical observation are not known. Growing evidence shows that dysregulation of MAPK pathways contributes to aging and neurodegenerative diseases; however, information about the upregulation of MAPKs in this context is still controversial. Among these kinases, ERK1 and ERK2 participate in the maintenance of proteostasis through the regulation of protein aggregation induced by endoplasmic-reticulum stress and other stress-mediated responses in the cell. Here, to assess the contribution of alterations of MEK1/2-ERK1/2 signaling-pathway activity to the development of AMD, we compared its changes with age in the retina of control (Wistar) rats and OXYS rats, which develop AMD-like retinopathy spontaneously. We showed that ERK1/2 signaling-pathway activity increases during physiological aging in the Wistar retina. The manifestation and dramatic progression of AMD-like pathology in OXYS rats co-occurred with hyperphosphorylation of ERK1/2 and MEK1/2 as key ERK1/2 signaling-pathway kinases in the retina. Besides, progression of the retinopathy was accompanied by ERK1/2-dependent tau protein hyperphosphorylation and enhancement of ERK1/2-dependent phosphorylation of CryaB at Ser45 in the retina.