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M. L. Mulhern, C. J. Madson, W. Thoreson, T. Shinohara; Chemical Chaperones and TUDCA Partially Suppress Degeneration of Retinal Photoreceptor Cells in Transgenic Mutant Rhodopsin S334ter-3 Rats. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2038.
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Retinitis pigmentosa (RP) is associated with mutant rhodopsin. We hypothesized that the mutant rhodopsin in the endoplasmic reticulum (ER) generates the unfolded protein response (UPR) in retinal photoreceptors. One purpose of this study was to investigate whether ER stress is induced in transgenic mutant rhodopsin S334ter-3 rats, which, in turn, would induce the UPR and result in degeneration of photoreceptors. In addition, the chemical chaperones 4-phenylbutyric acid (PBA), trimethylamine N-oxide dihydrate (TMAO) and tauroursodeoxycholic acid (TUDCA) are known to suppress ER stress. These drugs are reported to improve ER folding capacity, stabilize protein conformation, facilitate the trafficking of misfolded proteins, and promote cell survival. The second purpose of this study was to investigate whether these compounds can be used as therapeutic agents to suppress death of retinal photoreceptors in these rats.
Transgenic rats and 661W cells were kindly provided by Dr. Matthew La Vail (UCSF) and by Muayyad Al-Ubaidi (University of Oklahoma, OK), respectively. Two hundred and fifty to five hundred mg of chemical chaperones were administered to newly born rats twice a day by gavage or subcutaneous injection. Retinal slices were stained with calcein and ethidium homodimer-1 (EthD-1) to evaluate live and apoptotic cells. Protein blot analysis was used to identify UPR-specific proteins.
ER stressors activated UPR-specific proteins and induced cell death in 661W cells. S334ter-3 retinal slices demonstrated the production of reactive oxygen species (ROS) and photoreceptor cell death. UPR-specific proteins were upregulated in postnatal day 5 and 10 S334ter-3 rats. The chemical chaperones and TUDCA partially ameliorated death of S334ter-3 retinal photoreceptor cells.
The UPR appears to play a vital role in the transgenic mutant rhodopsin S334ter-3 rats. Chemical chaperones and TUDCA are able to partially suppress retinal photoreceptor cell death and subsequently delay RP formation in the transgenic S334ter-3 rats. Modulating ER stress and the UPR pathway by chemical chaperones may offer a therapeutic approach for RP in humans.
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