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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY020846-03S1
Application #
8516845
Study Section
Program Officer
Shen, Grace L
Project Start
2010-09-01
Project End
2015-05-31
Budget Start
2012-09-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$223,839
Indirect Cost
$79,427
Name
University of California San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Chiang, Wei-Chieh; Joseph, Victory; Yasumura, Douglas et al. (2016) Ablation of Chop Transiently Enhances Photoreceptor Survival but Does Not Prevent Retinal Degeneration in Transgenic Mice Expressing Human P23H Rhodopsin. Adv Exp Med Biol 854:185-91
Westenskow, Peter D; Bucher, Felicitas; Bravo, Stephen et al. (2016) iPSC-Derived Retinal Pigment Epithelium Allografts Do Not Elicit Detrimental Effects in Rats: A Follow-Up Study. Stem Cells Int 2016:8470263
Chan, Priscilla; Stolz, Julia; Kohl, Susanne et al. (2016) Endoplasmic reticulum stress in human photoreceptor diseases. Brain Res 1648:538-541
Kohl, Susanne; Zobor, Ditta; Chiang, Wei-Chieh et al. (2015) Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet 47:757-65
Salganik, Maxim; Sergeyev, Valeriy G; Shinde, Vishal et al. (2015) The loss of glucose-regulated protein 78 (GRP78) during normal aging or from siRNA knockdown augments human alpha-synuclein (α-syn) toxicity to rat nigral neurons. Neurobiol Aging 36:2213-23
Alavi, Marcel V; Chiang, Wei-Chieh; Kroeger, Heike et al. (2015) In Vivo Visualization of Endoplasmic Reticulum Stress in the Retina Using the ERAI Reporter Mouse. Invest Ophthalmol Vis Sci 56:6961-70
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
Lee, Bradford W; Kumar, Usha R; Lin, Jonathan H et al. (2015) Cysticercosis with an Orbital Tropism in Twins. Am J Trop Med Hyg 93:828-30
Hiramatsu, Nobuhiko; Chiang, Wei-Chieh; Kurt, Timothy D et al. (2015) Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death. Am J Pathol 185:1800-8
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

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