PURPOSE: The human rhodopsin (Rho) mutation T17M leads to autosomal dominant retinitis pigmentosa (adRP). The goal of our study was to elucidate the role of endoplasmic reticulum (ER) stress in retinal degeneration in hT17M Rho mice and identify potential candidates for adRP gene therapy. METHODS: We used transgenic mice expressing the ER stress-activated indicator (ERAI) and hT17M Rho to evaluate the activation of ER stress responses. Quantitative reverse transcription PCR (qRT-PCR) was used to analyze changes in the expression of 30 unfolded protein response (UPR)-associated genes at P12, 15, 18, 21, and 25. The cytosolic fraction of hT17M Rho retinal cells was used to measure the release of cytochrome C and apoptotic inducing factor-1 (AIF1) by Western blotting. Optical coherence tomography (OCT) analysis was performed for 1-month-old hT17M Rho mice. RESULTS: hT17M Rho was localized in the outer nuclear layer (ONL) of T17M(+/-)ERAI(+/-) photoreceptors as well as C57BL/6 retinas injected with AAV-hT17M Rho-GFP. In P15 hT17M Rho retinas, we observed an up-regulation of UPR genes (Atf4, Eif2α, Xbp1, Bip, Canx, and Hsp90), autophagy genes and proapoptotic Bcl2 genes. OCT, and the downregulation of Nrl and Crx gene expression confirmed that cell death occurs in 55% of photoreceptors via the up-regulation of caspase-3 and caspase-12, and the release of AIF1 from the mitochondria. CONCLUSIONS: 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.
PURPOSE: The humanrhodopsin (Rho) mutation T17M leads to autosomal dominant retinitis pigmentosa (adRP). The goal of our study was to elucidate the role of endoplasmic reticulum (ER) stress in retinal degeneration in hT17M Rho mice and identify potential candidates for adRP gene therapy. METHODS: We used transgenic mice expressing the ER stress-activated indicator (ERAI) and hT17M Rho to evaluate the activation of ER stress responses. Quantitative reverse transcription PCR (qRT-PCR) was used to analyze changes in the expression of 30 unfolded protein response (UPR)-associated genes at P12, 15, 18, 21, and 25. The cytosolic fraction of hT17M Rho retinal cells was used to measure the release of cytochrome C and apoptotic inducing factor-1 (AIF1) by Western blotting. Optical coherence tomography (OCT) analysis was performed for 1-month-old hT17M Rho mice. RESULTS: hT17M Rho was localized in the outer nuclear layer (ONL) of T17M(+/-)ERAI(+/-) photoreceptors as well as C57BL/6 retinas injected with AAV-hT17M Rho-GFP. In P15 hT17M Rho retinas, we observed an up-regulation of UPR genes (Atf4, Eif2α, Xbp1, Bip, Canx, and Hsp90), autophagy genes and proapoptotic Bcl2 genes. OCT, and the downregulation of Nrl and Crx gene expression confirmed that cell death occurs in 55% of photoreceptors via the up-regulation of caspase-3 and caspase-12, and the release of AIF1 from the mitochondria. CONCLUSIONS: 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.
Authors: Jingyung Hur; Daphne W Bell; Kathleen L Dean; Kathryn R Coser; Pablo C Hilario; Ross A Okimoto; Erica M Tobey; Shannon L Smith; Kurt J Isselbacher; Toshi Shioda Journal: Cancer Res Date: 2006-10-15 Impact factor: 12.701
Authors: Jonathan H Lin; Han Li; Douglas Yasumura; Hannah R Cohen; Chao Zhang; Barbara Panning; Kevan M Shokat; Matthew M Lavail; Peter Walter Journal: Science Date: 2007-11-09 Impact factor: 47.728
Authors: Fang Zhang; Robert B Hamanaka; Ekaterina Bobrovnikova-Marjon; John D Gordan; Mu-Shui Dai; Hua Lu; M Celeste Simon; J Alan Diehl Journal: J Biol Chem Date: 2006-08-07 Impact factor: 5.157
Authors: T Li; M A Sandberg; B S Pawlyk; B Rosner; K C Hayes; T P Dryja; E L Berson Journal: Proc Natl Acad Sci U S A Date: 1998-09-29 Impact factor: 11.205
Authors: Benjamin M Scott; Steven K Chen; Nihar Bhattacharyya; Abdiwahab Y Moalim; Sergey V Plotnikov; Elise Heon; Sergio G Peisajovich; Belinda S W Chang Journal: Genetics Date: 2018-12-04 Impact factor: 4.562
Authors: Anne R Murray; Linda Vuong; Daniel Brobst; Steven J Fliesler; Neal S Peachey; Marina S Gorbatyuk; Muna I Naash; Muayyad R Al-Ubaidi Journal: Hum Mol Genet Date: 2015-01-30 Impact factor: 6.150
Authors: Marcel V Alavi; Wei-Chieh Chiang; Heike Kroeger; Douglas Yasumura; Michael T Matthes; Takao Iwawaki; Matthew M LaVail; Douglas B Gould; Jonathan H Lin Journal: Invest Ophthalmol Vis Sci Date: 2015-10 Impact factor: 4.799
Authors: Heike Kroeger; Carissa Messah; Kelly Ahern; Jason Gee; Victory Joseph; Michael T Matthes; Douglas Yasumura; Marina S Gorbatyuk; Wei-Chieh Chiang; Matthew M LaVail; Jonathan H Lin Journal: Invest Ophthalmol Vis Sci Date: 2012-11-09 Impact factor: 4.799