Disruptions of Autophagy in the Rat Retina with Age During the Development of Age-Related-Macular-Degeneration-like Retinopathy.

Oyuna S Kozhevnikova,Mikhail A Tyumentsev,Nataliya G Kolosova,Darya V Telegina

doi:10.3390/ijms20194804

Abstract

Age-related macular degeneration (AMD) is one of the main causes of vision impairment in the elderly. Autophagy is the process of delivery of cytoplasmic components into lysosomes for cleavage; its age-related malfunction may contribute to AMD. Here we showed that the development of AMD-like retinopathy in OXYS rats is accompanied by retinal transcriptome changes affecting genes involved in autophagy. These genes are associated with kinase activity, immune processes, and FoxO, mTOR, PI3K-AKT, MAPK, AMPK, and neurotrophin pathways at preclinical and manifestation stages, as well as vesicle transport and processes in lysosomes at the progression stage. We demonstrated a reduced response to autophagy modulation (inhibition or induction) in the OXYS retina at age 16 months: expression of genes Atg5, Atg7, Becn1, Nbr1, Map1lc3b, p62, and Gabarapl1 differed between OXYS and Wistar (control) rats. The impaired reactivity of autophagy was confirmed by a decreased number of autophagosomes under the conditions of blocked autophagosome–lysosomal fusion according to immunohistochemical analysis and transmission electron microscopy. Thus, the development of AMD signs occurs against the background of changes in the expression of autophagy-related genes and a decrease in autophagy reactivity: the ability to enhance autophagic flux in response to stress.

Highlights

Age-related macular degeneration (AMD) is a multifactorial retinal neurodegenerative disease, one of major causes of severe irreversible vision loss in the elderly worldwide [1]
Functional annotation of the Differentially Expressed Genes (DEGs) in the retina of OXYS rats compared to Wistar rats at 20 days of age yielded gene ontology (GO) terms associated with protein phosphorylation, intracellular signal transduction, negative regulation of TOR signaling, TORC2 signaling, histone deacetylation, regulation of cell proliferation, and neuronal cell death (Table 1)
To assess the amount of lipofuscin-like aggregates and autophagic compartments and confirm the effective blockage of autophagy by CQ, we evaluated the ultrastructure of retinal pigment epithelium (RPE) cells in the retina of 16-month-old Wistar and OXYS rats from the following groups: control, 48 h fasting, CQ, and CQ48

Summary

Introduction

Age-related macular degeneration (AMD) is a multifactorial retinal neurodegenerative disease, one of major causes of severe irreversible vision loss in the elderly worldwide [1]. A complex interaction of multiple genetic and environmental factors leads to degeneration of photoreceptors, of the retinal pigment epithelium (RPE), and of Bruch’s membrane, as well as alterations in choroidal capillaries. A total of 80% of AMD patients have a diagnosis of the dry form of AMD, for which no effective treatment exists today [2]. During dry AMD, the loss of vision primarily involves progressive degeneration of macular RPE cells under the influence of the accumulation of lipofuscin and drusen; these alterations subsequently exert adverse effects on neurosensory layers of the retina [4]. Recent studies proved the critical role of macroautophagy in the homeostasis of aging RPE cells [5,6,7]

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