Purchase this article with an account.
Mansi M. Kunte, Shreyasi Choudhury, Vishal M. Shinde, Jessica F. Manhiem, Masayuki Miura, Oleg S. Gorbatyuk, Marina S. Gorbatyuk; ER Stress is Involved in Retinal Degeneration Induced by Human T17m Mutant Rhodopsin. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6453.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
The human rhodopsin (Rho) mutation T17M leads to autosomal dominant Retinitis Pigmentosa (adRP). The goal of this study is to elucidate the role of ER stress in retinal degeneration in hT17M Rho mice and identify potential candidates for adRP gene therapy.
We used transgenic mice expressing the ERAI (ER stress-activated indicator) and hT17M Rho to evaluate the activation of ER stress responses. qRT-PCR was used to analyze changes in the expression of 32 genes associated with ER stress and apoptosis at P12, 15, 18 and 21. Isolation of the cytosolic fraction of hT17M Rho retinal cells was used to measure the release of cytochrome C and AIF1 by western blotting. OCT analysis was performed to analyze retinas from 1-month-old hT17M Rho mice.
hT17M Rho was localized in the ONL of photoreceptors and lead to activation of the UPR in T17M+/-ERAI+/- mice at P15. At P15, we also observed an up-regulation of UPR genes (Atf4, Eif2alpha, Xbp1, Bip, Canx and Hsp90). The expression of autophagy genes and proapoptotic Bcl2 genes was significantly elevated in hT17M Rho mice starting at P15. OCT and the downregulation of Nrl and Crx gene expression confirmed that cell death occurs in 55% of photoreceptors via the up-regulation of caspase3 and caspase12 and the release of AIF1 from the mitochondria.
The ER stress response is involved in retinal degeneration in hT17M Rho mice. The final demise of photoreceptors occurs via apoptosis involving ER-stress-associated and mitochondria-induced caspase activation. We identified Atg5, Atg7, Bax, Bid, Bik and Noxa as potential therapeutic targets for adRP treatment.
This PDF is available to Subscribers Only