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John D Ash, Jerome E Roger, Elodie-Kim Grellier, Anand Swaroop, Katya Lobanova, Casey Keuthan; Universal Responses to Stress in Inherited Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3221.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal stress leading to rod degeneration is caused by a range of insults. Inherited degeneration alone is attributed to mutations in over 250 individual genes. The goal of this study was to investigate gene expression changes at the onset of degeneration in genetic mouse models of disease to identify common pathways involved in the retina’s early response to stress.
Bulk RNA-seq data from flow-sorted wild-type and Pde6bRd10 rods at ages P19 and P23 of Rho P23H mutant and control mice were analyzed. Differential expression analysis was performed using edgeR on the raw counts of each biological sample. Low-expressing genes were filtered out by Counts per Million (< 2 in all samples). A gene was considered differentially expressed if p < 0.05. Gene Ontology (GO) analysis of differentially expressed genes was completed using LAGO. The GO term lists were further refined and visualized using REVIGO. Additional KEGG pathway analysis was performed with DAVID.
Similar gene expression patterns were found between the different degenerative models. There was a clear downregulation of nearly all of the genes encoding for the rod phototransduction machinery. Many regulators of rod gene expression were also reduced in the stressed cells. Widespread changes in metabolic gene expression were another common finding among the stress models. AMPK signaling components, including activators of the energy sensor (e.g. Stk11, Adipor1, Camkk2) and targets of AMPK (e.g. Srebf1, Ppargc1a), were significantly dysregulated. Disruptions in genes specific to the function and maintenance of mitochondria were also evident.
Our data show that repression of visual perception genes and dysregulation of metabolism genes are common transcriptional signatures within retinal cells that precede rod death caused by inherited mutations. We hypothesize that attenuating expression of phototransduction components is part of the retina’s integrated stress response, mediated by factors like STAT3 to promote cell survival in stress conditions. Our data showing that AMPK signaling and mitochondria-related genes are dysregulated before the onset of cell death suggest that maintaining or restoring metabolic homeostasis could slow the progression of retinal disease. Overall, this study provides a greater understanding of how the retina universally responds to stress for the discovery of broad-spectrum targets for early therapeutic intervention.
This is a 2020 ARVO Annual Meeting abstract.
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