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.
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.
|Biswas, Pooja; Naeem, Muhammad Asif; Ali, Muhammad Hassaan et al. (2018) Whole-Exome Sequencing Identifies Novel Variants that Co-segregates with Autosomal Recessive Retinal Degeneration in a Pakistani Pedigree. Adv Exp Med Biol 1074:219-228|
|Branham, Kari; Guru, Aditya A; Kozak, Igor et al. (2018) Identification of Novel Deletions as the Underlying Cause of Retinal Degeneration in Two Pedigrees. Adv Exp Med Biol 1074:229-236|
|Chiang, Wei-Chieh; Chan, Priscilla; Wissinger, Bernd et al. (2017) Achromatopsia mutations target sequential steps of ATF6 activation. Proc Natl Acad Sci U S A 114:400-405|
|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|
|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|
|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|
|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|
|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|
|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|
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