Abstract
P62/SQSTM1, a multi-domain protein that regulates inflammation, apoptosis, and autophagy, has been linked to age-related pathologies. For example, previously we demonstrated that administration of p62/SQSTM1-encoding plasmid reduced chronic inflammation and alleviated osteoporosis and metabolic syndrome in animal models. Herein, we built upon these findings to investigate effect of the p62-encoding plasmid on an age-related macular degeneration (AMD), a progressive neurodegenerative ocular disease, using spontaneous retinopathy in senescence-accelerated OXYS rats as a model. Overall, the p62DNA decreased the incidence and severity of retinopathy. In retinal pigment epithelium (RPE), p62DNA administration slowed down development of the destructive alterations of RPE cells, including loss of regular hexagonal shape, hypertrophy, and multinucleation. In neuroretina, p62DNA prevented gliosis, retinal thinning, and significantly inhibited microglia/macrophages migration to the outer retina, prohibiting their subretinal accumulation. Taken together, our results suggest that the p62DNA has a strong retinoprotective effect in AMD.
Highlights
Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in industrialized countries [1]
To study age-associated disorders, we introduced a model of senescence-accelerated OXYS rats, which spontaneously develop a phenotype similar to human AMD-like retinopathy [5,6,7,8,9,10]
Statistical analysis showed that retinopathy continued to progress in both control and experimental groups but p62DNA reduced the severity of patho-logical changes in the eyeground of OXYS rats (p < 0.001)
Summary
Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in industrialized countries [1]. Significant pathological changes in the RPE as well as clinical signs of advanced stages of retinopathy are evident in OXYS rats older than 12 months [6, 10] These changes manifest themselves as excessive accumulation of lipofuscin and amyloid in the RPE regions [6], disturbances in the morphology of the RPE sheet, including an increase in the proportion of multinucleated cells, hypertrophy, distortion of cell shape, and reactive gliosis [10]. This animal model is successfully used to study the pathways and molecular alterations implicated in the development and progression of age-related diseases [11, 12] as well as to test new therapeutic interventions [8, 13, 14]. We assessed effects of p62DNA administration on the development of retinopathy in OXYS rats and evaluated possible mechanisms of its action
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