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The Role of Bip Co-Chaperone SIL1 in Marinesco-Sjögren Syndrome Pathogenesis" (2018)

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The Role of Bip Co-Chaperone SIL1 in Marinesco-Sjögren Syndrome Pathogenesis University of Tennessee Health Science Center UTHSC Digital Commons Theses and Dissertations (ETD) College of Graduate Health Sciences 12-2018 The Role of BiP Co-chaperone SIL1 in Marinesco- Sjögren Syndrome Pathogenesis Viraj Paresh Ichhaporia University of Tennessee Health Science Center Follow this and additional works at: https://dc.uthsc.edu/dissertations Part of the Medical Cell Biology Commons, and the Medical Molecular Biology Commons Recommended Citation Ichhaporia, Viraj Paresh (http://orcid.org/0000-0001-7466-6487), "The Role of BiP Co-chaperone SIL1 in Marinesco-Sjögren Syndrome Pathogenesis" (2018). Theses and Dissertations (ETD). Paper 469. http://dx.doi.org/10.21007/etd.cghs.2018.0470. This Dissertation is brought to you for free and open access by the College of Graduate Health Sciences at UTHSC Digital Commons. It has been accepted for inclusion in Theses and Dissertations (ETD) by an authorized administrator of UTHSC Digital Commons. For more information, please contact [email protected]. The Role of BiP Co-chaperone SIL1 in Marinesco-Sjögren Syndrome Pathogenesis Document Type Dissertation Degree Name Doctor of Philosophy (PhD) Program Biomedical Sciences Track Microbiology, Immunology, and Biochemistry Research Advisor Linda M. Hendershot, Ph.D. Committee Alessandra d'Azzo, Ph.D. Tony N. Marion, Ph.D. David R. Nelson, Ph.D. J. Paul Taylor, M.D., Ph.D. Stanislav S. Zakharenko, M.D., Ph.D. ORCID http://orcid.org/0000-0001-7466-6487 DOI 10.21007/etd.cghs.2018.0470 This dissertation is available at UTHSC Digital Commons: https://dc.uthsc.edu/dissertations/469 The Role of BiP Co-chaperone SIL1 in Marinesco-Sjögren Syndrome Pathogenesis A Dissertation Presented for The Graduate Studies Council The University of Tennessee Health Science Center In Partial Fulfillment Of the Requirements for the Degree Doctor of Philosophy From The University of Tennessee By Viraj Paresh Ichhaporia December 2018 Chapter 2 © 2015 by Viraj P. Ichhaporia et al. All other material © 2018 by Viraj P. Ichhaporia. All rights reserved. ii DEDICATION Dedicated to my parents and my grandparents. It is because of their countless sacrifices, unconditional love, and everlasting support that have inspired me to push beyond my personal limits, and who have instilled in me the values that I most cherish today. iii ACKNOWLEDGEMENTS It has been an incredible journey over the past seven years, studded with numerous memories and learning lessons, that brings me to the end of my dissertation. Right from my lab rotation to until now, I have never stopped learning from Dr. Linda M. Hendershot, my Ph.D. advisor, and I am indebted to her for that. Dr. Hendershot has been an excellent mentor over these years and is responsible for inculcating in me the core values of an ideal scientist, while always being supportive and enabling me to be a better version of myself, at a professional and a personal level. I am grateful to her for giving me the opportunity to be a part of the family at Hendershot laboratory and the cherished memories that I carry forward. I shall always remember what I have learnt here. Along with Dr. Hendershot, I am very thankful to Melissa Mann for teaching me the rigor and prowess with which scientific experimentation should be performed. It is Ms. Mann who taught me many of the lab techniques that I proudly claim as my ‘bread and butter’ skills. I also wish to thank her for her help with numerous aspects of my dissertation research. I am also thankful to my friends within the Hendershot lab, both past and present, for enlivening the work place and for always being supportive, encouraging, and helpful at any given opportunity. It is only because of them that the late nights and long hours passed by with ease. I thank Tyler Sanford for early discussions on the potential of this project and helping me transition into this research field. I thank Drs. Brian Murphy and Walid Awad for their assistance with managing the mouse colony and genotyping. I truly appreciate the support and constructive feedback I have received over the years from Dr. Kyung Tae Chung (who discovered mammalian SIL1), Dr. Joel Otero, Dr. Ethel Pereira, Dr. Matthias Feige, Dr. Julia Behnke, Dr. Jyoti Sinha, Dr. Greg Poet, Dr. Kristine Pobre, Dr. Amanda Preston, and Mary Carson Irvine. A special thanks to my friends and fellow graduate students, Christina Oikonomou and Rachael Wood, for their wholehearted support. I wish them the best for their own Ph.D. journeys. I was fortunate to work with an excellent summer student and a budding young scientist, Jessica Joyce, and thank her for her help with the SIL1 mutants project. I sincerely also thank my committee members, Dr. Alessandra d’Azzo, Dr. Tony Marion, Dr. David Nelson, Dr. J. Paul Taylor, and Dr. Stanislav Zakharenko, for their time, advice, guidance, and support over these years. The decision to pursue proteomics and many riveting answers stemmed from the scientific discussions during my committee meetings. I would like to thank Dr. Alessandra d’Azzo, Dr. Mondira Kundu, Dr. J. Paul Taylor, and Dr. Bo Wang for their generous gift of reagents, and Dr. Diantha Van de Vlekkert and Dr. Cath Drummond for their help with establishing myoblast cultures. Without the help from my collaborators, answering questions using technologies that lie beyond my expertise would not have been possible. In doing so, these collaborators not only offered me their time, but also excellent opportunities to educate myself and understand complex data in a meaningful manner. I thank Sharon Frase and Linda Horner for their assistance with electron microscopy studies; Dr. Peter Vogel, Sean iv Savage, Michael Anderson, Michael Straign, and Chandra Savage for their help animal pathology and pharmacokinetic studies; Dr. Junmin Peng, Dr. Vishwajeeth Pagala, Dr. Kanisha Kavdia, and Dr. Yong-Dong Wang for their help with proteomic studies; Dr. Jieun Kim and Dr. Walter Akers for their help with PET-μCT studies; Dr. Chunliang Li and Shaela Wright for making the CRISPR-mediated SIL1 knockout cell lines a possibility; Yumei Zhang for all her help with the structural analysis of the SIL1 mutants, and Dr. Fabio Demontis for providing critical feedback and improving our SIL1- myopathy article. I would like to acknowledge the funding support I have received from UTHSC and St. Jude in the form of travel grants that have enabled me to present my research on diverse platforms and engage in career development activities. For this, I thank Dr. Donald Thomason, Dr. Gerard Zambetti, and Dr. Isaac Donkor. I thank NIH and ALSAC for their funding support through Dr. Hendershot that has allowed me to perform my experimentation. I also thank the UTHSC deans along with the past and present members of the Graduate Student Executive Committee for empowering and supporting graduate students. I also appreciate the help I have received from the faculty and staff members at UTHSC and St. Jude. In particular, I would like to call out the current and past IBS Program Directors, Dr. Elizabeth Fitzpatrick, Dr. Rennolds Ostrom, and Dr. Pat Ryan; and Ms. Elizabeth Webb, Late Ms. Tricia Satkowski, and Ms. Denise Slaughter, our past and present program coordinators from UTHSC and St. Jude. I also thank the faculty members of the Microbiology, Biochemistry, and Immunology department, and my colleagues within the Tumor Cell Biology department for their scientific feedback and guidance. Lastly, I am grateful beyond measure to my family, especially my parents, without whom this life-changing journey would have never materialized, and for their ever-lasting support and inspiration. I am very thankful to my fiancé for being my northern star and my strength. Last, but certainly not the least, I would like to end by thanking my friends who made my time in Memphis a truly enjoyable and nostalgic experience. v ABSTRACT Marinesco-Sjögren syndrome (MSS) is a rare, autosomal recessive, multisystem disorder, which is characterized by cerebellar ataxia, early-onset bilateral cataracts, and progressive myopathy amongst other symptoms. MSS has been attributed to mutations in the SIL1 gene, which encodes a nucleotide exchange factor for the endoplasmic- reticulum-resident Hsp70 chaperone, BiP. To date, there are 46 MSS-associated mutations that have been reported in SIL1, which occur throughout this gene and are predicted to result in a loss of SIL1’s function. The large majority of these mutations cause deletions of large fractions of the SIL1 protein. Nine MSS-associated mutations are particularly interesting because they alter less than six amino acids, yet are associated with a phenotype indistinguishable from a near-full length deletion of SIL1. The mechanisms by which these nine mutations lead to a loss of SIL1’s function are not well understood. On the other hand, it remains unclear how the loss of SIL1 leads to the multisystem defects observed in MSS, selectively affecting certain tissues while sparing others. Our goal was to answer these two questions. We have shown that the selected nine MSS-associated SIL1 mutations may dramatically alter the protein microenvironment and disrupt intramolecular interactions, such that it alters the folding properties of SIL1 and renders it aggregation-prone. This offers a potential mechanism by which mutations in SIL1 cause a loss of its function. We validated that the C57BL/6 Sil1Gt mouse model, which harbors a genetic disruption of Sil1, phenocopies numerous aspects of the MSS-phenotype and represents a valid preclinical model system to investigate the MSS-associated pathology and explore pharmacotherapeutic strategies. Using a combination of the Sil1Gt mice and SIL1- deficient MSS-patient-derived lymphoblastoid cell lines, we explored the biosynthesis and secretion of immunoglobulins (Ig), which are the best characterized substrate of BiP to date. In vivo antigen-specific immunizations and ex vivo LPS stimulation of splenic B cells revealed that the Sil1Gt mouse was indistinguishable from wild-type age-matched controls, in terms of both the kinetics and magnitude of antigen-specific antibody responses.
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