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Early Mechanisms of Retinal Degeneration in the Harlequin Mouse Western University Scholarship@Western Electronic Thesis and Dissertation Repository 7-17-2014 12:00 AM Early Mechanisms of Retinal Degeneration in the harlequin Mouse Eric Dolinar The University of Western Ontario Supervisor Dr. Kathleen Hill The University of Western Ontario Graduate Program in Biology A thesis submitted in partial fulfillment of the equirr ements for the degree in Master of Science © Eric Dolinar 2014 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Biology Commons, Genetics Commons, and the Molecular Genetics Commons Recommended Citation Dolinar, Eric, "Early Mechanisms of Retinal Degeneration in the harlequin Mouse" (2014). Electronic Thesis and Dissertation Repository. 2156. https://ir.lib.uwo.ca/etd/2156 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. i Early Mechanisms of Retinal Degeneration in the harlequin Mouse (Thesis Format: Monograph) by Eric A Dolinar Graduate Program in Biology A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science The School of Graduate and Postdoctoral Studies The University of Western Ontario, London, Ontario, Canada © Eric A Dolinar 2014 i ii Abstract Retinal diseases are personally debilitating and expensive, yet many early disease mechanisms leading to their onset and progression remain poorly understood. The harlequin mouse is a model of human mitochondrial dysfunction and parainflammation leading to subsequent cerebellar and retinal degeneration. Diagnosis of retinal degeneration can be tracked in vivo and is associated with AIF dysfunction. Here, retinal dysfunction in the harlequin mouse was first quantified using electroretinography followed by assay of blood-retinal-barrier integrity and transcriptome alterations in young adulthood. Nonmetric multidimensional scaling of oscillatory potentials provided a novel, comprehensive assessment of inner-retinal health and can detect shifts in OP parameters. Barrier integrity ruled out confounding exogenous antigens and confirmed an endogenous source of retinal tissue malfunction. In addition, transcriptome alterations support the necessity of the hq retina to maintain metabolic demands. Alternative metabolism pathways are hypothesized to be important for hq complex I mitochondrial- dysfunction associated retinal degeneration. Keywords: harlequin, Apoptosis-inducing factor, retinal degeneration, mitochondrial dysfunction, electroretinography, oscillatory potentials, nonmetric multidimensional scaling, blood retina barrier, Evans Blue, ATP deficiency, quantitative gene expression, glycerol metabolism. ii iii Co-authorship Statement Eric Ammon Dolinar performed the following work under the supervision and financial support of Dr. Kathleen Allen Hill. This thesis is presented in monographic format. Eric Ammon Dolinar performed the experimental research presented in this thesis and will be a co-author on resulting publications. Dr. Kathleen Hill will be a senior author on all publications produced from this research due to her role in project design, supervision, literature research, data analysis and assistance with publication writing. Alex Laliberté, Thomas MacPherson, Anita Prtenjaca, Anson Li and Dr. C.M.L Hutnik will be co-authors on specialized papers produced from the research due to assistance in experimental design, gene expression array data or electroretinography and clinical relevance. iii iv Acknowledgements I would like to express my deepest appreciation and gratitude to all those who helped guide me through my Master’s degree. First and foremost, I would like to thank my supervisor, Dr. Kathleen Hill who provided me with moral, academic, scientific and motivational support throughout the duration of my project. Her positive attitude, knowledge, patience, encouragement and attention were essential to the progression and completion of this final thesis. I would also like to thank Dr. Robert Cumming and Dr. Denis Maxwell for their continuous positive feedback, insight, and critical evaluation as advisory committee members. In addition, I would like to acknowledge and show my appreciation to the staff at the LRGC, particularly David Carter, for his assistance and timely turnaround when I had projects that needed to be finished. I would like to thank all members of the Hill laboratory, past and present, for their technical assistance and friendship over the last two years. In particular, I would like to thank Anson Li for his willingness to work early mornings and late hours in order to assist me, as well as for his friendship outside of the lab. Finally I would like to thank my friends and family for their support and encouragement during all stages of my degree. A special thank you goes to my girlfriend, Marta Pajak and her family, for her unwavering support, patience, understanding and consolation that kept me grounded during stressful times. iv v Funding from the Plunkett Foundation, Canadian Glaucoma Society, Lawson Health Research Institute-Internal Research Fund, Canadian Institutes of Health Research, National Sciences and Engineering Research Council of Canada to Dr. Kathleen Hill supported the research in this thesis. Eric Dolinar was funded by an Ontario Graduate Scholarship and a travel award from the Department of Ophthalmology at Western University. v vi Table of Contents Abstract .............................................................................................................................. ii Co-authorship Statement ................................................................................................ iii Acknowledgements ...........................................................................................................iv Table of Contents ..............................................................................................................vi List of Figures ..................................................................................................................... x List of Tables ................................................................................................................... xii List of Appendices .......................................................................................................... xiii List of Abbreviations ......................................................................................................xiv Chapter 1. Introduction .................................................................................................... 1 1.1 Increased prevalence of neurodegenerative disorders in an increasingly aged population ................. 1 1.2 Mechanisms of common retinal degenerative diseases remain unclear ................................................ 2 1.3 The physiology and anatomy of a healthy retina is complex ................................................................. 3 1.4 Phototransduction is compromised in retinal degeneration .................................................................. 8 1.5 Neuronal homeostasis is maintained by glial cells of the retina ........................................................... 9 1.6 Retinal neurons rely heavily of oxidative phosphorylation for ATP generation ................................. 10 1.7 Nourishment in the retina is maintained by a healthy blood-retinal-barrier ...................................... 11 1.8 Electrophysiological examination can assess health of the visual system in vivo ............................... 12 1.9 Oscillatory potentials can provide early in vivo examination of INL and GCL function .................... 15 1.10 Nonmetric multidimensional scaling as a method for understanding OP waveform changes .......... 17 1.11 Mitochondrial dysfunction is a common theme in retinal degeneration ........................................... 19 1.12 The mouse is a valuable model organism for vision research ........................................................... 19 1.13 The harlequin (hq) mouse is a model of mitochondrial dysfunction and neurodegenerative disease 20 1.14 Timeline of the hq disease progression ............................................................................................. 22 1.15 Deficiencies in OXPHOS lead to neuronal malfunction and ATP deficiencies ................................. 23 1.16 OXPHOS deficiencies in the hq mouse .............................................................................................. 24 1.17 Parainflammation is a chronic response in the hq retina.................................................................. 26 vi vii 1.18 Central hypothesis ............................................................................................................................. 29 1.19 Experimental Aims............................................................................................................................. 29 Chapter 2. Materials and Methods................................................................................. 34 2.1 Animal care and housing ..................................................................................................................... 34 2.2 Genotyping of the hq allele .................................................................................................................. 34 2.3 Collection of trace
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