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Michael Butler, Hongwei Ma, Fan Yang, Xi-Qin Ding; Mouse Models of Rapid and Progressive Cone Degeneration Display Key Differences in Autophagy Signaling. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2489. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
When subjected to metabolic or organellar stress, cells respond by activating key stress signaling pathways, such as autophagy. In addition to attempting to correct the insult and return to homeostasis, these responses help determine cell fate. Mouse models of inherited retinal degenerative diseases have been shown to experience both metabolic and organellar stress, but the mediators of these responses have not been fully studied in inherited cone dystrophies. This work investigated the potential contributions of autophagy signaling in determining photoreceptor fate in rapid versus progressive cone degeneration.
Rpe65-/-/Nrl-/- mice (RPE65 deficiency on a cone-dominant background) were used to model rapid cone degeneration, whereas Cnga3-/-/Nrl-/-, Cngb3-/-/Nrl-/-, and Gucy2e-/-/Nrl-/- mice (CNGA3, CNGB3, and RetGC1 deficiency on a cone-dominant background, respectively) were used to model progressive cone degeneration. Expression levels of several autophagy genes were analyzed by qRT-PCR at ages postnatal day 15 (P15) and P30 in all genotypes. In addition, western blot analysis of autophagy mediators and autophagosome formation protein markers was performed.
Expression levels of autophagy genes showed similar trends among progressive cone degeneration phenotypes at P30, with significant increases in Atg7, LC3a, and LC3b, when compared with genotype-matched P15 levels. However, Rpe65-/-/Nrl-/- mice showed significant down-regulation in nearly all autophagy gene markers at P30 when compared with P15 levels. Interestingly, lipidated LC3b protein levels were increased at P30 in both Rpe65-/-/Nrl-/- and Cnga3-/-/Nrl-/- mice, suggesting enhanced autophagosome formation. In addition, intermediate autophagy markers Atg7 and Beclin1 displayed significantly different trends between Rpe65-/-/Nrl-/- and Cnga3-/-/Nrl-/- mice at P30.
In mouse models of rapid and progressive cone degeneration, we demonstrate that autophagy signaling is significantly different between these phenotypes, specifically involving intermediate autophagy proteins that may determine the type of autophagic response. The findings of this study provide insight into mechanisms mediating rapid versus progressive cone death in inherited cone dystrophies, as well as identifying potential sites of intervention to target autophagy signaling and preserve rapidly degenerating cones.
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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