Spinal Muscular Atrophy : Evidence of a Multi-System Disease
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Spinal muscular atrophy : Evidence of a multi-system disease Marc-Olivier Deguise This thesis is submitted as a partial fulfillment of the Ph.D. program in Cellular and Molecular Medicine of the University of Ottawa September 6th 2019 Department of Cellular and Molecular Medicine Faculty of Medicine University of Ottawa © Marc-Olivier Deguise, Ottawa, Canada, 2020 Authorization The content of this document consists of Marc-Olivier Deguise’s original work. All previously published work as produced by Marc-Olivier Deguise & al. obtained permissions from the publishers for publication within this document, whether unaltered or modified. Licenses are provided below. 1. Deguise M.O. & al. (20XX) Myopathic phenotype precedes neuronal phenotype in a new mild mouse model of spinal muscular atrophy (Not yet submitted) 2. Deguise M.O. & al. (20XX). Spinal muscular atrophy: providing a novel framework to elucidate NAFLD molecular pathogenesis (Not yet submitted). 3. Marc-Olivier Deguise & al. (2019) Low fat diets increase survival of a mouse model of spinal muscular atrophy. Ann Clin Transl Neurol (IF: 4.656). DOI : 10.1002/acn3.50920 This is an open access article under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. If you remix, transform or build upon the material, you may not distribute the modified material. This work has been altered as part of the thesis. II 4. Deguise M.O. & al. (2019) Abnormal fatty acid metabolism is a core component of spinal muscular atrophy. Ann Clin Transl Neurol (IF: 4.656). DOI : 10.1002/acn3.50855 This is an open access article under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. If you remix, transform or build upon the material, you may not distribute the modified material. This work has been altered as part of the thesis. 5. Deguise M.O. & Kothary R. (2019) Chapter 2: Spinal muscular atrophy. Chromatin signalling and Neurological disorders. Edited by Olivier Binda, Elsevier The license number of this permission to reproduce this work is 4718220143434 and the terms and conditions can be found here. 6. Deguise M.O. and Kothary R. (2017) New insights into SMA pathogenesis: Immune dysfunction and neuroinflammation. Ann Clin Transl Neurol (IF: 4.656). 4(7):522-530 Doi:10.1002/acn3.423 This is an open access article under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), III which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. If you remix, transform or build upon the material, you may not distribute the modified material. This work has been altered as part of the thesis. 7. Deguise M.O. & al. (2017) Immune dysregulation may contribute to disease pathogenesis in spinal muscular atrophy mice. Human molecular genetics (IF: 5.689). 26(4):801-819. doi: 10.1093/hmg/ddw434 Oxford University Press Rights department: “As part of your copyright agreement with Oxford University Press you have retained the right, after publication, to use all or part of the article and abstract, in the preparation of derivative works, extension of the article into a booklength work, in a thesis/dissertation, or in another works collection, provided that a full acknowledgement is made to the original publication in the journal. As a result, you should not require direct permission from Oxford University Press to reuse your article.” 8. Deguise M.O. & al. (2017) Chapter 10: Contributions of different cell types to SMA pathogenesis. Spinal Muscular Atrophy: Disease Mechanisms and Therapy, Edited by: C. J. Sumner, S. Paushkin and C.-P. Ko, Elsevier, ISBN: 978-0-12- 803685-3 The license number of this permission to reproduce this work is 4621921478892 and the terms and conditions can be found here. IV 9. Deguise M.O. & al. (2016) Differential induction of muscle atrophy pathways in two mouse models of spinal muscular atrophy. Scientific Reports (IF: 4.259). 6:28846 | DOI: 10.1038/srep28846 This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third-party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ V Abstract Spinal muscular atrophy (SMA) is a devastating recessive neurological disorder thought to be affecting primarily the motor neurons. As such, paralysis, motor weakness and death ensue. While SMA is most commonly seen in infants and children, it can span all ages. Its genetic etiology revolves around the homozygous deletion or mutation of the SMN1 gene, whose product (SMN protein) has critical and ubiquitous roles in mRNA splicing, amongst various other functions in mRNA metabolism. As such, SMN depletion in other non- neuronal cells type is likely to have physiological repercussions, and perhaps modulate the SMA phenotype. Herein, we identify the molecular pathways of atrophy in skeletal and cardiac muscle of two mouse models of SMA and their therapeutic modulation via the histone deacetylase inhibitor trichostatin A. We also identify dramatic changes in immune organs in mouse models of SMA, which could impact susceptibility to infections. Furthermore, we establish the presence of important defects in fatty acid homeostasis in the liver and plasma seen in both mouse models and SMA patients. Finally, we provide the first mild mouse model of SMA that reliably reproduces canonical features of SMA, permitting aging studies. This model presents with a prominent myopathic phenotype prior to motor neuron death, without extra-neuronal involvement during the course of its lifespan. Overall, our work shows multiple potentially clinically relevant defects in extra- neuronal organs, provides ways to abrogate them and provides a framework to study them over the course of aging. VI AUTHORIZATION ...................................................................................................................................... II ABSTRACT ................................................................................................................................................. VI LIST OF TABLES .................................................................................................................................... XIV LIST OF FIGURES .................................................................................................................................. XVI LIST OF ABBREVIATIONS .................................................................................................................. XXI ACKNOWLEDGEMENTS ................................................................................................................ XXVIII CHAPTER 1 : GENERAL INTRODUCTION ........................................................................................... 1 CONTRIBUTION ............................................................................................................................................ 2 SPINAL MUSCULAR ATROPHY: PREVALENCE, GENETIC BASIS AND CLINICAL FEATURES ............................. 3 THE SMN PROTEIN: UBIQUITOUS LOCALIZATION AND FUNCTIONS .............................................................. 5 HISTORICAL PERSPECTIVE: SKELETAL MUSCLE PROVIDE FIRST EVIDENCE OF EXTRA-NEURONAL DEFECTS 8 The hunt for the defective cell type: Motor neurons vs. Skeletal muscles .............................................. 8 Cell culture: Separating the muscle from the motor neuron ............................................................................... 8 Lessons on muscle defects from conditional mouse KnocKouts of SMN ......................................................... 10 Restoration of SMN in specific compartments confirm that all components of the motor unit, including muscles, are important ..................................................................................................................................................... 11 SKELETAL MUSCLE DEFECTS IN SMA ........................................................................................................ 12 Reduced SMN protein leads to embryonic and neonatal muscle growth impairment ......................... 12 Potential modulators of post-natal muscle growth in SMA .................................................................. 13 Satellite stem cell dysfunction and impaired myogenesis ................................................................................ 13 Anabolism and Catabolism in SMA ................................................................................................................. 16 Physiological defects in muscles of SMA mice ..................................................................................... 18 MULTI-ORGAN