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J. H. Lin, J. Kim, M. S. Gorbatyuk, K. Ahern, M. T. Matthes, D. Yasumura, A. S. Lewin, M. M. LaVail; Chop Expression in Transgenic Animal Models of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4466.
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Protein misfolding in the endoplasmic reticulum activates a set of signaling pathways, collectively termed the Unfolded Protein Response (UPR). UPR signaling promotes cell survival by reducing misfolded protein levels. UPR signaling also promotes cell death if protein misfolding persists, partly through upregulation of proapoptotic genes such as Chop. We have examined the expression of the Chop gene in the slowly evolving P23H-2 transgenic rhodopsin rat model of retinitis pigmentosa, as well as in a transgenic mouse line expressing the human T17M rhodopsin gene.
Retinas from transgenic rats expressing P23H rhodopsin were collected at multiple ages prior to and during retinal photoreceptor degeneration (postnatal day [P] 6, 8, 10, 12, 30 and 60). Photoreceptor cell loss is first seen at approximately P60 in P23H-2 rats. Retinas from Tg mice expressing T17M rhodopsin were collected at multiple postnatal timepoints (P3, P5, P7, P12, P18, P23, and P60). RNA was extracted and quantitative PCR was performed to measure the levels of specific gene targets.
The Chop gene selectively increased in Tg P23H-2 rhodopsin animals but remained low in wild-type animals at equivalent ages. The rise in Chop mRNA corresponded tightly with the rate of retinal degeneration in the P23H-2 rhodopsin animals and preceded frank loss of photoreceptor cells. We also present results from a similar analysis of transgenic T17M rhodopsin animals.
Proapoptotic UPR signaling is observed in retinas from transgenic models of autosomal dominant retinitis pigmentosa arising from mutant P23H rhodopsin expression. Increased UPR proapoptotic activity occurs prior to overt loss of photoreceptor cells. UPR signaling may link rhodopsin misfolding in photoreceptors to retinal degeneration.
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