The most common cause of inherited blindness is retinitis pigmentosa (RP), a family of diseases with various forms of inheritance caused by mutations in more than 45 genes. Over 100 distinct mutations have been identified in the rhodopsin gene that lead to RP. Many of these mutations cause rhodopsin protein misfolding and retention within the endoplasmic reticulum (ER). The cellular and molecular processes that link rhodopsin misfolding and ER retention to photoreceptor cell death are not well understood. During our previous research period, we investigated the role of the unfolded protein response (UPR) in retinal degeneration. The UPR comprises a set of cellular signaling pathways that detects misfolded proteins in the ER and promotes cell survival by reducing misfolded protein levels. However, if protein misfolding persists, the UPR switches to promote apoptosis. Here, we provide data that mutant rhodopsin linked to RP activates the UPR in vitro and in animal models of RP and that selective manipulation of UPR signaling can prevent cell death in vitro. Based on these findings, we hypothesize that ER stress and UPR signaling play important causal roles in determining photoreceptor cell survival in response to rhodopsin protein misfolding. To test this hypothesis, we will 1) investigate how UPR signaling regulates rhodopsin protein folding;2) test if we can enhance photoreceptor cell survival in vivo by artificial control of UPR;and 3) determine how mutant rhodopsin expression changes ER structure and morphology in photoreceptors. These studies will provide important molecular, cellular, and genetic insights into the pathogenesis of retinitis pigmentosa arising from mutant rhodopsin expression. These studies may also provide new therapeutic targets to prevent blindness.

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Mutations in rhodopsin leading to protein misfolding cause many types of retinitis pigmentosa leading to inherited blindness and severely impairing quality of life. We study the cellular, molecular, and genetic processes that link rhodopsin misfolding to retinitis pigmentosa with the goal of developing new therapies to prevent this devastating disease.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Shen, Grace L
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University of California San Diego
Schools of Medicine
La Jolla
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Chiang, Wei-Chieh; Kroeger, Heike; Sakami, Sanae et al. (2015) Robust Endoplasmic Reticulum-Associated Degradation of Rhodopsin Precedes Retinal Degeneration. Mol Neurobiol 52:679-95
Kroeger, Heike; LaVail, Matthew M; Lin, Jonathan H (2014) Endoplasmic reticulum stress in vertebrate mutant rhodopsin models of retinal degeneration. Adv Exp Med Biol 801:585-92
Muller, Karra; Lin, Jonathan H (2014) Orbital granulomatosis with polyangiitis (Wegener granulomatosis): clinical and pathologic findings. Arch Pathol Lab Med 138:1110-4
Hiramatsu, Nobuhiko; Messah, Carissa; Han, Jaeseok et al. (2014) Translational and posttranslational regulation of XIAP by eIF2? and ATF4 promotes ER stress-induced cell death during the unfolded protein response. Mol Biol Cell 25:1411-20
Joshi-Barr, Shivanjali; Bett, Cyrus; Chiang, Wei-Chieh et al. (2014) De novo prion aggregates trigger autophagy in skeletal muscle. J Virol 88:2071-82
Gorbatyuk, Marina S; Shabashvili, Arseniy; Chen, Weijun et al. (2012) Glucose regulated protein 78 diminishes ?-synuclein neurotoxicity in a rat model of Parkinson disease. Mol Ther 20:1327-37
Kroeger, Heike; Chiang, Wei-Chieh; Lin, Jonathan H (2012) Endoplasmic reticulum-associated degradation (ERAD) of misfolded glycoproteins and mutant P23H rhodopsin in photoreceptor cells. Adv Exp Med Biol 723:559-65
Chiang, Wei-Chieh; Messah, Carissa; Lin, Jonathan H (2012) IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin. Mol Biol Cell 23:758-70
Shinde, Vishal M; Sizova, Olga S; Lin, Jonathan H et al. (2012) ER stress in retinal degeneration in S334ter Rho rats. PLoS One 7:e33266
Gorbatyuk, Marina S; Gorbatyuk, Oleg S; LaVail, Matthew M et al. (2012) Functional rescue of P23H rhodopsin photoreceptors by gene delivery. Adv Exp Med Biol 723:191-7

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