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Tiziana Cogliati, Jennifer Barb, Norimoto Gotoh, Matthew Brooks, Linn Gieser, Neel Gupta, Rafael Villasmil, Inhan Lee, Peter Munson, Anand Swaroop; Down-regulation of oxidative phosphorylation genes and up-regulation of protein degradation pathway genes are a hallmark of aging rod photoreceptors in mouse retina. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4566.
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© ARVO (1962-2015); The Authors (2016-present)
Decreased visual function in the expanding aging population has a significant impact on the quality of life and health care. Aging is the major risk factor for visual impairment in the elderly and it has been suggested to be in part under genetic control. In the retina, photoreceptors become progressively dysfunctional with age. Thus, using the mouse as a model, we sought to investigate through global profiling of gene expression whether there are genetic determinants of aging-associated decline in rod photoreceptor function.
We selected five time-points, from 3 month old (mo) to 18 mo to be able to observe progressive changes during aging. We obtained highly enriched rod cell preparations by flow sorting dissociated retinal cells from Nrlp-EGFP mice, in which EGFP is expressed under the control of Nrl promoter in all rod photoreceptors throughout their lifespan. To maximize the statistical power of inferring changes in gene expression, we adopted two expression profiling platforms: Affymetrix exon array and Illumina high throughput directional RNA sequencing (RNAseq).
Combined regression analysis of the exon array and RNAseq data generated a list of 242 genes with progressively increased (n=129) or decreased (n=113) expression from 3 mo to 18 mo. Gene ontology and pathway analyses revealed a remarkable and almost unique over-representation of genes involved in oxidative phosphorylation in the down-regulated group and of genes encoding signaling molecules, in particular of the ubiquitination pathway, in the up-regulated group. Prediction of microRNAs with the capacity to bind to the candidate aging genes suggested the existence of regulatory and functional interaction networks.
While earlier studies have suggested that oxidative stress is a key determinant of rod dysfunction with aging, we show for the first time altered expression of genes encoding components of oxidative phosphorylation and signaling pathways that help cellular adaptation during aging-associated stress. Our studies provide greater insights into the molecular mechanisms involved in photoreceptor dysfunction in aging and allow a better design of rational interventions for age-related retinal and macular diseases.
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