Retinitis Pigmentosa is a group of inherited disorders that show a progressive loss of retinal function. One of the most common causes of Autosomal Dominant Retinitis Pigmentosa (ADRP) are mutations in the rhodopsin gene that disrupt its encoded protein's folding property. Our long-term goal is to understand how cells respond to stress caused by such rhodopsin proteins once they are synthesized in the endoplasmic reticulum (ER). As most cells have robust quality control mechanisms that can help eliminate such misfolded proteins from the ER, a better understanding of these mechanisms may have therapeutic implications. We focus on two specific ER quality control mechanisms that can help suppress retinal degeneration caused by misfolded rhodopsins. First is ER-Associated Degradation (ERAD), which refers to the ubiquitin-mediated degradation of misfolded proteins from the ER. Stimulation of ERAD can suppress retinal degeneration in a Drosophila model for ADRP, but the underlying mechanism remains poorly understood. In addition, ADRP may be suppressed by an intracellular signaling pathway activated by ER-stress, known as the Unfolded Protein Response (UPR). A central branch of the UPR is mediated by the unconventional splicing of xbp1 mRNA in the cytoplasm, leading to the synthesis of an active xbp1 transcription factor. Among the transcription targets of xbp1 include regulators of ERAD. To investigate mechanisms by which ERAD and the UPR suppress retinal degeneration in animal models of ADRP, we plan to use a combination of classical Drosophila genetics, cell biological analysis and high throughput RNAi assays. Specifically, we plan to investigate the precise mechanism by which misfolded rhodopsins are detected by the ERAD machinery and imported into the cytoplasm for degradation. In addition, we plan to study how the xbp1-mediated UPR pathway is regulated. We will test a specific hypothesis where xbp1 mRNA splicing is modulated by a specific phosphatase, and this phosphatase is in turn regulated by a regulatory subunit that binds to xbp1 mRNA. Any new genes or mechanisms identified through this approach will be examined for possible effects on retinal degeneration in a Drosophila model for ADRP, where an endogenous mutation in a rhodopsin encoding gene triggers a dominant form of age-related retinal degeneration. As the fly model shows a striking degree of similarity with the human condition, we believe that a successful outcome of this study may directly influence the development of new strategies against ADRP in humans.

Public Health Relevance

Mutations in the rhodopsin gene are responsible for approximately a quarter of autosomal dominant forms of Retinitis Pigmentosa (ADRP), a genetic disease that leads to blindness in individuals 40 ~ 60 years of age. Thus, a better understanding of the mechanisms that help the elimination of misfolded rhodopsins may have a direct impact on developing new therapeutic strategies against this 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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Neuhold, Lisa
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New York University
Anatomy/Cell Biology
Schools of Medicine
New York
United States
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Vasudevan, Deepika; Ryoo, Hyung Don (2016) Detection of Cell Death in Drosophila Tissues. Methods Mol Biol 1419:131-44
Mollereau, B; Rzechorzek, N M; Roussel, B D et al. (2016) Adaptive preconditioning in neurological diseases - therapeutic insights from proteostatic perturbations. Brain Res 1648:603-616
Kang, Kwonyoon; Ryoo, Hyung Don; Park, Jung-Eun et al. (2015) A Drosophila Reporter for the Translational Activation of ATF4 Marks Stressed Cells during Development. PLoS One 10:e0126795
Wang, Lifen; Ryoo, Hyung Don; Qi, Yanyan et al. (2015) PERK Limits Drosophila Lifespan by Promoting Intestinal Stem Cell Proliferation in Response to ER Stress. PLoS Genet 11:e1005220
Jang, Bo-Yun; Ryoo, Hyung Don; Son, Jaekyoung et al. (2015) Role of Drosophila EDEMs in the degradation of the alpha-1-antitrypsin Z variant. Int J Mol Med 35:870-6
Ryoo, Hyung Don (2015) Drosophila as a model for unfolded protein response research. BMB Rep 48:445-53
Vasudevan, Deepika; Ryoo, Hyung Don (2015) Regulation of Cell Death by IAPs and Their Antagonists. Curr Top Dev Biol 114:185-208
Wang, Lifen; Zeng, Xiankun; Ryoo, Hyung Don et al. (2014) Integration of UPRER and oxidative stress signaling in the control of intestinal stem cell proliferation. PLoS Genet 10:e1004568
Zhang, Tianyi; Liao, Yang; Hsu, Fu-Ning et al. (2014) Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities. PLoS Genet 10:e1004357
Coelho, Dina S; Cairrão, Fatima; Zeng, Xiaomei et al. (2013) Xbp1-independent Ire1 signaling is required for photoreceptor differentiation and rhabdomere morphogenesis in Drosophila. Cell Rep 5:791-801

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