Endoplasmic Reticulum Stress in Retinal Degeneration
Principal Investigator: Jonathan Lin
Affiliation: University of California
Abstract: The most common cause of inherited blindness is retinitis pigmentosa, a family of diseases with various forms of inheritance caused by mutations in more than 45 genes. The rhodopsin gene has more than 100 distinct mutations, and many forms of autosomal dominant retinitis pigmentosa (adRP) involve abnormal rhodopsin folding in which the misfolded protein is retained in the endoplasmic reticulum. However, it is not known how misfolded rhodopsin leads to the photoreceptor degeneration seen in the disease. The unfolded protein response (UPR) comprises a set of cellular signaling pathways present in all mammalian cells that detects misfolded proteins in the endoplasmic reticulum and directs protective and apoptotic actions taken by the cell. UPR signaling acts cytoprotectively by elevating chaperone levels; elevating ubiquitin-proteasome system activity; and reducing protein translation, all of which cumulatively decrease misfolded protein levels. UPR signaling can also trigger apoptosis through mitochondrial-dependent cytochrome C release and downstream activation of caspase-dependent protease cascades. This proposal investigates the role of UPR signaling in the pathogenesis of adRP using tissue culture systems and transgenic animal models of P23H-rhodopsin adRP. Specifically, this project aims to: 1) Determine the mechanism by which the photoreceptor senses misfolded rhodopsin, 2) Determine how rhodopsin misfolding lead to apoptosis, and 3) Test if modulation of the UPR can prevent misfolded rhodopsin-induced cell death. Dr. Jonathan Lin, the principal investigator, is an M.D., Ph.D., who received his graduate degree in neuroscience, completed his residency training in anatomic pathology, and wishes to develop the skills necessary to become an independent physician-scientist. The sponsor, Dr. Peter Walter, discovered the Unfolded Protein Response and has a strong record of training successful physician-scientist investigators. The co-sponsor, Dr. Matthew LaVail, is an expert in vision biology and retinal degeneration, and created and characterized the P23H-rhodopsin transgenic rat models of adRP.
Funding Period: 2007-08-01 - 2008-05-31
more information: NIH RePORT
- IRE1 signaling affects cell fate during the unfolded protein responseJonathan H Lin
Howard Hughes Medical Institute, University of California at San Francisco, San Francisco, CA 94158, USA
Science 318:944-9. 2007..Key findings from our studies in cell culture were recapitulated in photoreceptors expressing mutant rhodopsin in animal models of retinitis pigmentosa...
- Selective activation of ATF6 and PERK endoplasmic reticulum stress signaling pathways prevent mutant rhodopsin accumulationWei Chieh Chiang
Department of Pathology, University of California at San Diego, La Jolla, California, USA
Invest Ophthalmol Vis Sci 53:7159-66. 2012..The aim of this study was to investigate how ATF6 and PERK signaling affected misfolded rhodopsin in cells, which could identify new molecular therapies to treat retinal diseases associated with ER protein misfolding...
- Induction of endoplasmic reticulum stress genes, BiP and chop, in genetic and environmental models of retinal degenerationHeike Kroeger
Department of Pathology, University of California, San Diego, La Jolla, California, USA
Invest Ophthalmol Vis Sci 53:7590-9. 2012....
- T-cell infiltration in autosomal dominant neovascular inflammatory vitreoretinopathyVinit B Mahajan
Vitreoretinal Service, Department of Ophthalmology and Visual Sciences, The University of Iowa Hospitals and Clinics, Iowa City, IA, USA
Mol Vis 16:1034-40. 2010..Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a familial blinding disease of unknown pathophysiology. The eyes and sera from patients with ADNIV were studied to understand the immune response in this condition...
- Regulated Ire1-dependent decay of messenger RNAs in mammalian cellsJulie Hollien
Department of Biology, University of Utah, Salt Lake City, UT 84112, USA
J Cell Biol 186:323-31. 2009..Our data suggest that cells use a multitiered mechanism by which different conditions in the ER lead to distinct outputs from Ire1...
- Endoplasmic reticulum stress in disease pathogenesisJonathan H Lin
Department of Biochemistry, University of California, San Francisco, CA 94143, USA
Annu Rev Pathol 3:399-425. 2008..This review provides background information on the unfolded protein response and discusses a selection of diseases whose pathogenesis involves ER stress...
- BAX inhibitor-1 is a negative regulator of the ER stress sensor IRE1alphaFernanda Lisbona
Institute of Biomedical Sciences, FONDAP Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile
Mol Cell 33:679-91. 2009..Our results suggest a role for BI-1 in early adaptive responses against ER stress that contrasts with its known downstream function in apoptosis...
- Restoration of visual function in P23H rhodopsin transgenic rats by gene delivery of BiP/Grp78Marina S Gorbatyuk
Department of Molecular Genetics, University of Florida, Gainesville, FL 32610, USA
Proc Natl Acad Sci U S A 107:5961-6. 2010..Thus, the preservation of photoreceptor function resulting from elevated levels of BiP is due to suppression of apoptosis rather than to a promotion of rhodopsin folding...
- ER stress in retinal degeneration in S334ter Rho ratsVishal M Shinde
Department of Cell Biology and Anatomy, University of North Texas Health Science Center, North Texas Eye Research Institute, Fort Worth, Texas, United States of America
PLoS ONE 7:e33266. 2012..Therefore, two major cross-talking pathways, the UPR and mitochondrial MPTP occur in S334ter-4 Rho retina concomitantly and eventually promote the death of the photoreceptor cells...
- IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsinWei Chieh Chiang
Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA
Mol Biol Cell 23:758-70. 2012..Our findings reveal the diversity of proteolytic mechanisms used by IRE1 to eliminate misfolded rhodopsin...
- Rescue of photoreceptor degeneration by curcumin in transgenic rats with P23H rhodopsin mutationVidyullatha Vasireddy
Jacobs Retina Center, Department of Ophthalmology, University of California San Diego, La Jolla, California, United States of America
PLoS ONE 6:e21193. 2011..This data also suggest that curcumin may serve as a potential therapeutic agent in treating RP due to the P23H rhodopsin mutation and perhaps other degenerative diseases caused by protein trafficking defects...
- Misfolded proteins and retinal dystrophiesJonathan H Lin
Department of Pathology, University of California, San Diego, CA 92093 0612, USA
Adv Exp Med Biol 664:115-21. 2010..Last, we review new therapies for these diseases based on preventing protein misfolding in the retina...
- Monitoring and manipulating mammalian unfolded protein responseNobuhiko Hiramatsu
Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA
Methods Enzymol 491:183-98. 2011....
- Divergent effects of PERK and IRE1 signaling on cell viabilityJonathan H Lin
Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA
PLoS ONE 4:e4170. 2009..These results demonstrate that extended PERK and IRE1 signaling have opposite effects on cell viability. Differential activation of PERK and IRE1 may determine life or death decisions after ER protein misfolding...