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Rhodopsin Mutations Leading to Retinitis Pigmentosa

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Rhodopsin Mutations Leading to Retinitis Pigmentosa Investigation of the molecular mechanisms underlying the retinal degeneration observed in the P347S mutant rhodopsin model of retinitis pigmentosa A dissertation Submitted by Katherine M. Malanson In partial fulfillment of the requirements for the degree of Doctor of Philosophy In Neuroscience TUFTS UNIVERSITY Sackler School of Graduate Biomedical Sciences August 2011 Advisor: Janis Lem ii ABSTRACT Retinitis pigmentosa (RP) is a genetically heterogeneous group of diseases that causes blindness. RP can be inherited as an X-linked, autosomal recessive or autosomal dominant disease. Mutations within the rhodopsin gene account for approximately 25% of autosomal dominantly inherited RP cases. Therefore understanding the mechanisms causing rhodopsin-mediated RP has a significant health impact. To date, results from multiple labs indicate that rhodopsin-mediated RP pathogenesis does not share a common mechanism of degeneration. There is strong evidence that multiple mechanisms are involved, including protein misfolding, mislocalization, release of toxic products and aberrant signaling. This thesis investigates the molecular mechanisms involved in the retinal degeneration of the P347S mutant rhodopsin mouse model of retinitis pigmentosa. Through the use of transgenic animal models the involvement of persistent photosignaling, aberrant rhodopsin-arrestin complexes, chromophore toxicity and galectin-1 in retinal degeneration are investigated. Additionally, the involvement of glycogenes are investigated with a custom gene microarray. iii ACKNOWLEDGEMENTS I would like to first and foremost thank my advisor, Janis Lem. Without her this work would not have been possible. I am grateful to my committee members, Jim Schwob, Dan Jay and Noorjahan Panjwani, for their guidance throughout my time at Tufts. Additionally, I would like to thank my outside examiner, Clint Makino, for carefully reading my thesis and providing valuable feedback. I am indebted to my fellow lab members, Kibibi Ganz, Jinsong Yang, Fang Yang, Ed Dudek and Jesse Peterson. They provided helpful advice and daily scientific support. Additionally, I need to thank Zhiyi Cao and Anna Markowska of the Panjwani Lab for guiding me through the exciting world of glycobiology. I would like to thank the students of the Neuroscience Program at Tufts University Sackler School of Biomedical Sciences. Having the joy of being their peer kept me motivated even when experiments were not working. I would also like to express my gratitude to those who offered their expertise scientifically, including Tiansen Li for providing the P347S and K296E mutant rhodopsin mutant mouse lines, and Wolfgang Baehr for providing the VPP mutant mice. Thanks to Flore Celestin of the Specialized Center of Research in Ischemic Heart Disease Histology Core and Derek Papalegis of the Division of Animal Laboratory Medicine for assistance with histological sections. Special thanks to Basil Pawlyk and Mike Sandberg of Massachusetts Eye and Ear Infirmary for their help recording electroretinograms. iv Finally, a very special thanks to my family and my husband, Jeffrey, who have instilled in me a passion for learning, a drive for excellence, and a sense of humor and perspective to make this work not only possible, but worthwhile. This work was financially supported by The Synapse Neurobiology Training Grant, Program in Neuroscience, Tufts University School of Medicine; CFG grant support (National Institute of General Medical Sciences Grant GM62116), Foundation Fighting Blindness, National Eye Institute, Research to Prevent Blindness, and Massachusetts Lions Eye Research Fund. v TABLE OF CONTENTS Acknowledgements iii List of Tables vi List of Figures vi Chapter 1: An Introduction to Rhodopsin-Mediated Retinitis Pigmentosa 2 Chapter 2: A Novel Form of Transducin-Dependent Retinal Degeneration: Accelerated Retinal Degeneration in the Absence of Rod Transducin 46 Chapter 3: Involvement of Galectin-1 in Rhodopsin-Mediated Retinitis Pigmentosa 69 Chapter 4: Analysis of Glycogenes and their Molecular Pathways in Rhodopsin-Mediated Retinitis Pigmentosa by Microarray 100 Chapter 5: A Discussion of the Molecular Mechanisms Underlying P347S Mutant Rhodopsin Mediated-Retinitis Pigmentosa 123 Figures 144 Bibliography 209 vi LIST OF TABLES Table 1: Compiled ERG Data Table 2: Number of differentially expressed transcripts in P347S mutant rhodopsin retina compared to control Table 3: Categories of differentially expressed transcripts in P347S mutant rhodopsin retina over time Table 4: Differentially expressed transcripts involved in glycan degradation Table 5: Growth factor and receptor differentially expressed transcripts Table 6: Glycosyltransferases differentially expressed transcripts Table 7: Mouse Housekeeping differentially expressed transcripts Table 8: Chemokine differentially expressed transcripts Table 9: Interleukin and receptors differentially expressed transcripts Table 10: Additional differentially expressed transcripts Table 11: Trends of transcripts differentially expressed at 1 and 2 Months vii LIST OF FIGURES Figure 1: Schematic of the mammalian eye Figure 2: Retina structure Figure 3: Phototransduction cascade Figure 4: Rhodopsin secondary structure and point mutations associated with ADRP Figure 5: P23H difference spectra Figure 6: Cone cell death mechanisms: involvement of rod-derived trophic factor Figure 7: Gene therapy: The use of ribozymes to treat P23H rats Figure 8: Comparison of rhodopsin mutant mice on wild-type (Tr ) and -transducin null (Tr ) genetic backgrounds. Figure 9: Role of rhodopsin-arrestin complexes in P347S mutant rhodopsin degeneration. Figure 10: -transducin stabilizes P347S metarhodopsin. Figure 11: Comparison of A2E and A2E-precursor levels in wild-type and P347S mutant rhodopsin retinas Figure 12: P347S mutant rhodopsin protein has decreased stability Figure 13: Comparison of galectin-1 RNA levels in P347S mutant rhodopsin retinas compared to control Figure 14: Galectin-1 protein expression is increased in the P347S mutant rhodopsin retina compared to control Figure 15: Galectin-1 sugar-binding column identifies tenascin-R (TN-R) as a galectin-1 binding partner Figure 16: Mass-spectrophotometry identified peptides within TN-R Sequence viii Figure 17: Tenascin-R localizes to synaptic layers in the wild-type and galectin-1 knockout retina Figure 18: Tenascin-R expression in wild-type and P347S mutant rhodopsin retinas Figure 19: Morphology of P347S mutant rhodopsin retinas in the presence and absence of galectin-1 at 2M Figure 20: Morphology of P347S mutant rhodopsin retinas in the presence and absence of galectin-1 at 4M Figure 21: Morphology of P347S mutant rhodopsin retinas in the presence and absence of galectin-1 at 9M Figure 22: Involvement of galectin-1 in retinal degeneration measured with electroretinogram at 4M Figure 23: Time-to-Peak for 4M ERG Figure 24: Involvement of galectin-1 in retinal degeneration measured with electroretinogram at 9M Figure 25: Time-to-peak for 9M ERG Figure 26: Galectin-1 localization in wild-type control and galectin-1 knockout mice. Figure 27: Verification of galectin-1 antibody for immunoprecipitation. Figure 28: Identification of sugar independent galectin-1 binding partners Figure 29: Validation of galectin-1 binding with thy-1. Figure 30: Confirmation of galectin-1 sugar-binding with neuropilin-1 (NP-1) and tenascin-C (TN-C) Figure 31: Dendogram showing hierarchical clustering analysis of mutant and control retinas. ix Figure 32: Categories of differentially expressed transcripts in P347S mutant rhodopsin retina compared to control Figure 33: Comparison of microarray and quantitative RT-PCR data for CX3 chemokine receptor (CX3CR1) Figure 34: Comparison of microarray and quantitative RT-PCR data for colony stimulating factor 1 (CSF1) Figure 35: Localization of colony stimulating factor 1 (CSF1) in wild-type and P347S mutant rhodopsin retinas Figure 36: Comparison of microarray and quantitative RT-PCR data for colony stimulating factor 1 receptor (CSF1R) Figure 37: Localization of colony stimulating factor 1 receptor (CSF1R) in wild-type and P347S mutant rhodopsin retina Figure 38: Comparison of microarray and quantitative RT-PCR data for interleukin 6 signal transducer (IL6ST) 1 INVESTIGATION OF THE MOLECULAR MECHANISMS UNDERLYING THE RETINAL DEGENERATION OBSERVED IN THE P347S MUTANT RHODOPSIN MODEL OF RETINITIS PIGMENTOSA 2 CHAPTER 1: AN INTRODUCTION TO RHODOPSIN-MEDIATED RETINITIS PIGMENTOSA Portions of this chapter originally appeared as a chapter in Progress in Molecular Biology and Translational Science (Malanson and Lem 2009). 3 ABSTRACT Retinitis pigmentosa (RP) is a genetically and phenotypically heterogeneous group of diseases that cause blindness. RP is genetically inherited as an X-linked, autosomal recessive or autosomal dominant disease. Mutations within the rhodopsin gene account for approximately 25% of autosomal dominantly inherited RP cases. Therefore understanding the mechanisms causing rhodopsin-mediated RP has a significant health impact. To date, results from multiple labs indicate that rhodopsin- mediated RP pathogenesis does not share a common mechanism of degeneration. There is strong evidence that multiple mechanisms are involved, including impaired protein folding and localization, release of toxic products and aberrant signaling. Development of effective treatments requires investigation of the mechanisms involved in the degeneration caused by different rhodopsin mutations. This chapter focuses on the mechanisms by
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