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Targeted Proteomics and Biochemical Fractionation: New Tools for Deciphering the Synapse in Schizophrenia

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Targeted Proteomics and Biochemical Fractionation: New Tools for Deciphering the Synapse in Schizophrenia University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2012 Targeted Proteomics and Biochemical Fractionation: New Tools for Deciphering the Synapse in Schizophrenia Matthew Luke MacDonald University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Behavioral Neurobiology Commons, and the Nanoscience and Nanotechnology Commons Recommended Citation MacDonald, Matthew Luke, "Targeted Proteomics and Biochemical Fractionation: New Tools for Deciphering the Synapse in Schizophrenia" (2012). Publicly Accessible Penn Dissertations. 478. https://repository.upenn.edu/edissertations/478 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/478 For more information, please contact [email protected]. Targeted Proteomics and Biochemical Fractionation: New Tools for Deciphering the Synapse in Schizophrenia Abstract Schizophrenia is a chronic and debilitating psychiatric illness affecting approximately 1% of the world's population for which there is no cure and treatment options are limited. Poor understanding of disease pathology and the difficulty in modeling psychiatric symptoms in animal models has hindered the search for a cure. Despite these difficulties eatgr progress has been made on several fronts. Genetic studies have identified risk genes for disease, while fMRI and histology experiments have located brain regions with altered activity and cytoarchitecture. Pharmacology, molecular and immunology studies have identified receptor signaling pathways that are perturbed as well. One of the biggest challenges currently facing the field is elucidating the mechanisms linking genetic and environmental risk to the altered processes observed in the brains of schizophrenic patients. One approach to this question may be to investigate the postmortem brain tissues of patients. The goal of this thesis is to use mass spectrometry based proteomics to investigate the expression and partitioning of postsynaptic density proteins in these tissues. The postsynaptic density is implicated in disease pathology by genetic, cytoarchitecture and molecular studies. Thus, there is a good possibility that its protein composition reflects the crossroads of genetic risk and dysregulated molecular and developmental processes. A qualitative analysis of the human postsynaptic density was performed to catalog the proteins therein. Data from this experiment was harnessed to develop a mass spectrometry method for the targeted quantification of over 200 synaptic proteins. This method was then used to validate subcellular fractionation of human postmortem brain tissue to capture synaptic microdomains. Finally, this targeted mass spectrometry method was utilized to quantify synaptic protein expression and PSD partitioning in postmortem brain tissues of subjects and patients. The enrichment of PSD proteins was elevated in tissue from schizophrenic subjects compared to controls, while total protein expression was unaltered. This data suggests that partitioning, not expression, of postsynaptic proteins is altered in schizophrenia. The results of this study demonstrate the power of a targeted mass spectrometry approach and provide an important context in which to study the dysregulation of synaptic processes in schizophrenia. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Pharmacology First Advisor Chang-Gyu Hahn Second Advisor Ian A. Blair Keywords Human brain tissue, Neuroplasticity, Proteomics, Schizophrenia Subject Categories Behavioral Neurobiology | Nanoscience and Nanotechnology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/478 TARGETED PROTEOMICS AND BIOCHEMICAL FRACTIONATION: NEW TOOLS FOR DECIPHERING THE SYNAPSE IN SCHIZOPHRENIA Matthew L. MacDonald A Dissertation In Pharmacology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2012 Supervisor of Dissertation: Signature: . Chang-Gyu Hahn, MD, PhD, Associate Professor of Psychiatry Co-supervisor of Dissertation: Signature: . Ian A. Blair, PhD, A.N. Richards Professor of Pharmacology Graduate Group Chairperson: Signature: . Vladimir Muzykantov, MD, PhD, Professor of Pharmacology Dissertation Committee: David Manning, PhD, (Committee Chair) Professor of Pharmacology Harry Ischiropoulos, PhD, Research Professor of Pediatrics James Eberwine, PhD, Professor of Pharmacology David Lynch, MD, Associate Professor of Neurology and Pediatrics Steven E. Arnold, Professor of Psychiatry and Neurology DEDICATION To my parents, For their inspiration and support “Home. Home was BAMA, the Sprawl, the Boston-Atlanta Metropolitan Axis. Program a map to display frequency of data exchange, every thousand megabytes a single pixel on a very large screen. Manhattan and Atlanta burn solid white. Then they start to pulse, the rate of traffic threatening to overload your simulation. Your map is about to go nova. Cool it down. Up your scale. Each pixel a million megabytes. At a hundred million megabytes per second, you begin to make out certain blocks in midtown Manhattan, outlines of hundred-year-old industrial parks ringing the old core of Atlanta...” - William Gibson, Neuromancer ii ACKNOWLEDGMENTS This work would have been impossible without the support of more people than I likely have space to thank, but I shall try anyway. First I would like to thank my thesis advisors, Drs. Chang-Gyu Hahn and Ian Blair for their continued support, the examples they set and the mentorship they provided. I am forever in the debt of Dr. Anamika Banerjee and Dr. Gene Ciccimaro, whose instruction in biochemistry and mass spec were second to none. Thanks to Dr. Karin Borgmann-Winter for always being there, ready to spring into action and handle a last minute anything. Drs. Anastasia Yocum and Colin Barry were my first mentors in the Blair lab and have continued to provide excellent advice to this day. Dr. Jason Covy, Dr. Angela Wehr and Dr. Bobby Basu are also deserving of thanks for their companionship and support both inside and outside of the lab. Also, I must include a special thanks to Christine Shwed for helming the battleship that is the Blair lab and for always knowing how to navigate the byzantine Upenn bureaucracy. There are several collaborators who contributed to this work and are deserving of recognition. Dr. Jonathan Trinidad provided indispensable advice during my early days of working with the PSD. Dr. Jumin Peng and Dr. Nicholas Seyfried supplied the AQUA peptide standards that fueled early quantitative work. Dr. Tilo Grosser and Angel Pizzaro provided informatics support for the initial discovery experiments. Dr. Scott Hemby graciously provided the pristine rhesus monkey tissue used in this work. Dr. Steve Seeholzer, a recent collaborative partner, provided the informatics analysis in Chapter 4. The ex-vivo stimulation experiments that opened the door for this work, and will likely provide for its validation, were conducted by Dr. Hoau-Yan Wang. Finally, I would like to thank all the members of the Hahn and Blair labs during my tenure. The generosity of ThermoScientific and Eksigent was also essential, as they provided us with SEED LC-MS instrumentation to develop and validate the methodology described in this work. I would like to thank Darlene Murphy and Amol Praskatesh from ThermoScientific and Tristan Williams and Donna duPont at Eksigent. These individuals were instrumental in supporting our application for a SEED instrument. iii I would also like to thank my thesis committee members, Dr. David Manning, Dr. Harry Ischiropoulos, Dr. James Eberwine, Dr. David Lynch and Dr. Steven E. Arnold for taking the time to provide valuable feedback at my committee meetings. All I can say is that your advice was great, your predictions usually correct and I should have heeded them both more often. I must also thank the patients and their families for donating their bodies to science, so that those who come after them may find relief from this difficult disease. Without their generosity and sacrifice this research would be impossible. I would be remiss not to thank the National Institute of Mental Health and the Stanley Medical Research Foundation for funding my education and research. Finally, I would like to thank my statistically significant other, Kathy Totoki, whose understanding of my late nights in the lab, and more importantly, exceptional command of both the English language and neuropharmacology have been indispensable throughout this process. iv ABSTRACT TARGETED PROTEOMICS AND BIOCHEMICAL FRACTIONATION: NEW TOOLS FOR DECIPHERING THE SYNAPSE IN SCHIZOPHRENIA Matthew L. MacDonald Advisors: Chang-Gyu Hahn Ian A. Blair Schizophrenia is a chronic and debilitating psychiatric illness affecting approximately 1% of the world’s population for which there is no cure and treatment options are limited. Poor understanding of disease pathology and the difficulty in modeling psychiatric symptoms in animal models has hindered the search for a cure. Despite these difficulties great progress has been made on several fronts. Genetic studies have identified risk genes for disease, while fMRI and histology experiments have located brain regions with altered activity and cytoarchitecture. Pharmacology, molecular and immunology studies have identified receptor signaling pathways that are perturbed as well. One of the biggest challenges
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