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Jingyu Yao, Lin Jia, Eric Frontera, Naheed Khan, Debra A Thompson, David N Zacks; Hyperautophagy in response to protein misfolding contributes to photoreceptor cell death in Pro23His-rhodopsin mice. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2487.
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© ARVO (1962-2015); The Authors (2016-present)
The Pro23His (P23H) variant resulting from a mutation in the rhodopsin gene is a common cause of autosomal dominant retinitis pigmentosa (adRP). In both the human disease and the P23H mouse, rhodopsin misfolding results in accumulation of rhodopsin aggregates. The purpose of this study is to define the role of autophagy in retinal degeneration in the P23H mouse and to understand the mechanisms of protein degradation needed to maintain photoreceptor (PR) homeostasis and survival.
Basal levels of autophagic activity in P23H mice and C57BL/6 controls, measured by western blot and immunohistochemical (IHC) analysis, were compared as a function of age. The effect of modulating autophagy on retinal degeneration in the P23H mouse was evaluated by pharmacologically activating autophagy using a derivative of rapamycin (CCI-799), and by genetically inhibiting autophagy by deleting Atg5 in rod cells to generate the P23H-Atg5Δrod mouse. Retinal structure and function were evaluated by IHC and ERG analysis. Proteasome activity, a compensatory mechanism for degrading misfolded proteins, was measured by chymotrypsin-like activity assay, and compared across P23H, P23H-Atg5Δrod and C57BL/6 mice.
Retinas from P23H mice showed increased autophagy flux as evidenced by elevated levels of LC3-II under conditions in which autophagosome-lysosome fusion was blocked. P23H mice treated with CCl-799 exhibited increased rates of PR degeneration, whereas deletion of autophagy in rod cells (P23H-Atg5Δrod mouse) resulted in PR preservation with a corresponding increase in PR function. The level of proteasome activity was significantly higher in the P23H-Atg5Δrod mouse retina than in P23H mouse.
Elevated autophagy levels in the P23H mouse retina, and the rescue of the P23H phenotype by deletion of autophagy, suggest that misfolded rhodopsin results in hyper-autophagy in rods. Although autophagy is important for clearing misfolded rhodopsin, persistent autophagy activation contributes to PR cell death. The absence of autophagy shifts the degradation of misfolded rhodopsin to the proteasome and is protective in P23H mice. These observations provide new understanding of the role of autophagy in PR death due to rhodopsin folding mutations, and suggest that modulating the flux of misfolded protein from autophagy to the proteasome may represent an important therapeutic option.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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