Increased Sensitivity to Light-Induced Damage in a Mouse Model of Autosomal Dominant Retinal Disease

Da, White; Jj, Fritz; Ww, Hauswirth; Kaushal, Shalesh; Lewin, Alfred S.

doi:10.1167/iovs.06-1131

Cited by 55 publications

(57 citation statements)

References 36 publications

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“…Thus, the observation of an increased level of cleaved caspase-7 (up to fourfold) in P23H-3 RHO retina is not surprising. Photoreceptors are known to die by apoptosis in this model (28). Our studies have therefore demonstrated the importance of the UPR in clinically relevant model of a human disease.…”

Section: Discussionsupporting

confidence: 53%

Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78

Gorbatyuk¹,

Knox²,

LaVail

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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249

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The P23H mutation within the rhodopsin gene (RHO) causes rhodopsin misfolding, endoplasmic reticulum (ER) stress, and activates the unfolded protein response (UPR), leading to rod photoreceptor degeneration and autosomal dominant retinitis pigmentosa (ADRP). Grp78/BiP is an ER-localized chaperone that is induced by UPR signaling in response to ER stress. We have previously demonstrated that BiP mRNA levels are selectively reduced in animal models of ADRP arising from P23H rhodopsin expression at ages that precede photoreceptor degeneration. We have now overexpressed BiP to test the hypothesis that this chaperone promotes the trafficking of P23H rhodopsin to the cell membrane, reprograms the UPR favoring the survival of photoreceptors, blocks apoptosis, and, ultimately, preserves vision in ADRP rats. In cell culture, increasing levels of BiP had no impact on the localization of P23H rhodopsin. However, BiP overexpression alleviated ER stress by reducing levels of cleaved pATF6 protein, phosphorylated eIF2α and the proapoptotic protein CHOP. In P23H rats, photoreceptor levels of cleaved ATF6, pEIF2α, CHOP, and caspase-7 were much higher than those of wild-type rats. Subretinal delivery of AAV5 expressing BiP to transgenic rats led to reduction in CHOP and photoreceptor apoptosis and to a sustained increase in electroretinogram amplitudes. We detected complexes between BiP, caspase-12, and the BH3-only protein BiK that may contribute to the antiapoptotic activity of BiP. Thus, the preservation of photoreceptor function resulting from elevated levels of BiP is due to suppression of apoptosis rather than to a promotion of rhodopsin folding.autosomal dominant retinitis pigmentosa | endoplasmic reticulum stress | adeno-associated virus | unfolded protein response

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Section: Discussionsupporting

confidence: 53%

Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78

Gorbatyuk¹,

Knox²,

LaVail

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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249

272

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“…These results imply that in vivo, a misfolded monomer of P23H opsin can also induce co-aggregation with WT rhodopsin preventing rod outer segment (ROS) formation. This dominant negative effect on ROS formation has been considered as the underlying reason for the adRP inheritance of P23H in humans.The retinal structure in heterozygous transgenic mice and rats expressing the P23H opsin partially mimics that of adRP in humans carrying this mutation (15)(16)(17)(18)(19). Mislocalization of the P23H opsin in the retina also has been reported in transgenic animal models (20), and this causes an abnormally reduced response to light (21).…”

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confidence: 88%

“…The retinal structure in heterozygous transgenic mice and rats expressing the P23H opsin partially mimics that of adRP in humans carrying this mutation (15)(16)(17)(18)(19). Mislocalization of the P23H opsin in the retina also has been reported in transgenic animal models (20), and this causes an abnormally reduced response to light (21).…”

mentioning

confidence: 88%

Probing Mechanisms of Photoreceptor Degeneration in a New Mouse Model of the Common Form of Autosomal Dominant Retinitis Pigmentosa due to P23H Opsin Mutations

Sakami

Maeda

Bereta³

et al. 2011

Journal of Biological Chemistry

230

362

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Rhodopsin, the visual pigment mediating vision under dim light, is composed of the apoprotein opsin and the chromophore ligand 11-cis-retinal. A P23H mutation in the opsin gene is one of the most prevalent causes of the human blinding disease, autosomal dominant retinitis pigmentosa. Although P23H cultured cell and transgenic animal models have been developed, there remains controversy over whether they fully mimic the human phenotype; and the exact mechanism by which this mutation leads to photoreceptor cell degeneration remains unknown. By generating P23H opsin knock-in mice, we found that the P23H protein was inadequately glycosylated with levels 1-10% that of wild type opsin. Moreover, the P23H protein failed to accumulate in rod photoreceptor cell endoplasmic reticulum but instead disrupted rod photoreceptor disks. Genetically engineered P23H mice lacking the chromophore showed accelerated photoreceptor cell degeneration. These results indicate that most synthesized P23H protein is degraded, and its retinal cytotoxicity is enhanced by lack of the 11-cisretinal chromophore during rod outer segment development.Greater understanding of a genetically heterogeneous group of retinal disorders is now possible due to the results of studies that have revealed their causative genes. Many genetic loci can cause such retinopathies (RetNet) (1). Mutations in phototransduction genes, including those in opsin genes (2), constitute one of the major known causes of inherited blinding diseases (3). Among them, retinitis pigmentosa (RP) 2 refers to a group that displays genetic heterogeneity and a range of clinical phenotypes (4). RP manifested predominantly by death of rod photoreceptor cells is a progressive disease characterized by night blindness that progresses to loss of peripheral vision and eventually all useful vision over decades (5). Of more than 100 mutant opsins associated with autosomal dominant RP (adRP), the most frequent mutation is P23H (6), accounting for ϳ10% of human cases (7,8).In vitro studies have shown that the P23H opsin associated with adRP is misfolded and retained in the ER (9 -12). Consequently, this protein is not transported to the cell membrane (12) but instead was degraded by the ubiquitin-proteosome system (13). Co-expression of adRP-linked opsin folding-deficient mutants and wild type (WT) opsin resulted in enhanced proteosome-mediated degradation and steady-state ubiquitination of both mutant and WT opsin in an experimental cell line (14). These results imply that in vivo, a misfolded monomer of P23H opsin can also induce co-aggregation with WT rhodopsin preventing rod outer segment (ROS) formation. This dominant negative effect on ROS formation has been considered as the underlying reason for the adRP inheritance of P23H in humans.The retinal structure in heterozygous transgenic mice and rats expressing the P23H opsin partially mimics that of adRP in humans carrying this mutation (15)(16)(17)(18)(19). Mislocalization of the P23H opsin in the retina also has been reported in transgenic ani...

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“…Mutations of these residues or their surrounding glycosylation consensus sequences (T4K, N15S, and T17M) are linked to a subset of RP known as sector RP in which the inferior retina is primarily affected, potentially attributable to greater light exposure to this region (Fishman et al, 1992;Sullivan et al, 1993;Li et al, 1994;van den Born et al, 1994). Furthermore, both transgenic mice expressing human T17M rhodopsin (White et al, 2007) and a naturally occurring dog model harboring a rhodopsin T4R mutation exhibit lightsensitive retinal degeneration (Kijas et al, 2002;Cideciyan et al, 2005). Together, the human disease and animal models suggest that glycosylation plays a crucial role in the structure and/or function of rhodopsin.…”

Section: Introductionmentioning

confidence: 99%

The Role of Rhodopsin Glycosylation in Protein Folding, Trafficking, and Light-Sensitive Retinal Degeneration

Tam¹,

Moritz²

2009

J. Neurosci.

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Several mutations in the N terminus of the G-protein-coupled receptor rhodopsin disrupt NXS/T consensus sequences for N-linked glycosylation (located at N2 and N15) and cause sector retinitis pigmentosa in which the inferior retina preferentially degenerates. Here we examined the role of rhodopsin glycosylation in biosynthesis, trafficking, and retinal degeneration (RD) using transgenic Xenopus laevis expressing glycosylation-defective human rhodopsin mutants. Although mutations T4K and T4N caused RD, N2S and T4V did not, demonstrating that glycosylation at N2 was not required for photoreceptor viability. In contrast, similar mutations eliminating glycosylation at N15 (N15S and T17M) caused rod death. Expression of T17M was more toxic than T4K to transgenic photoreceptors, further suggesting that glycosylation at N15 plays a more important physiological role than glycosylation at N2. Together, these results indicate that the structure of the rhodopsin N terminus must be maintained by an appropriate amino acid sequence surrounding N2 and may require a carbohydrate moiety at N15. The mutant rhodopsins were rendered less toxic in their dark inactive states, because RD was abolished or significantly reduced when transgenic tadpoles expressing T4K, T17M, and N2S/N15S were protected from light exposure. Regardless of their effect on rod viability, all of the mutants primarily localized to the outer segment and Golgi and showed little or no endoplasmic reticulum accumulation. Thus, glycosylation was not crucial for rhodopsin biosynthesis or trafficking. Interestingly, expression of similar bovine rhodopsin mutants did not cause rod cell death, possibly attributable to greater stability of bovine rhodopsin.

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Increased Sensitivity to Light-Induced Damage in a Mouse Model of Autosomal Dominant Retinal Disease

Cited by 55 publications

References 36 publications

Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78

Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78

Probing Mechanisms of Photoreceptor Degeneration in a New Mouse Model of the Common Form of Autosomal Dominant Retinitis Pigmentosa due to P23H Opsin Mutations

The Role of Rhodopsin Glycosylation in Protein Folding, Trafficking, and Light-Sensitive Retinal Degeneration

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