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Investigating SPTLC1 Mutations on Protein and Lipid Profiles in HSN-I

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Investigating SPTLC1 Mutations on Protein and Lipid Profiles in HSN-I Investigating mitochondrial and ER protein profiles of cells expressing SPTLC1 mutations Scott Stimpson Thesis submitted for the award of Doctor of Philosophy Supervisor: Dr. Simon Myers Associate Supervisor: Prof. Jens Coorssen Associate Supervisor: Assoc. Prof. Paul Witting Neuro-Cell Biology Laboratory Molecular Medicine Research Group School of Science and Health Western Sydney University Australia STATEMENT OF AUTHENTICATION I Scott Stimpson declare that this thesis contains no material that has been accepted for the award of any other degree or diploma and that, to the best of my knowledge and belief, this thesis contains no material previously published or written by another person, except where due reference has been made in the text of this thesis. August 2015 S.E. Stimpson BMedSci (Hons) ii | Page ABSTRACT Axonal degeneration is the final common path in many neurological disorders. It is seen in its pure form in hereditary axonal neuropathies. The hereditary neuropathies are the most common group of diseases. Subsets of neuropathies involving the sensory neuron are known as hereditary sensory neuropathies (HSNs). Hereditary sensory neuropathy type I (HSN-I) (the most common subtype of HSNs) is an autosomal dominant inherited disorder, characterised by the progressive degeneration of the dorsal root ganglion and with onset of clinical symptoms occurring between the second or third decade of life. Heterozygous mutations in the serine palmitoyltransferase (SPT) long chain subunit 1 (SPTLC1) have been identified as the cause of HSN-I. In Paper I, we optimised an isolation method of mitochondria to allow the production of a full and in-depth proteomic profile to elucidate the molecular mechanisms underlying mitochondrial (dys) function in HSN-I. Paper II, detailed examinations of a small sub-set of proteins that were found to be altered in abundance within harvested mitochondria from HSN-I mutant SPTLC1 cells. Comparison of mitochondrial protein isolates from control and patient lymphoblasts, showed an increased abundance of Ubiquinol Cytochrome C Reductase Core Protein 1, an electron-transport chain protein, as well as the immunoglobulin, Ig Kappa Chain C. In, Paper III, endoplasmic reticulum (ER) protein lysates from HSN-I patient and control lymphoblasts, were examined leading to identification of changes in expression of five proteins; Hypoxia Up regulated Protein 1, Chloride Intracellular Channel Protein 1, Ubiqutin-40s Ribosomal Protein S27a, Coactosin and Ig Kappa chain C. iii | Page Further investigations into mitochondrial and ER protein profiles were carried out in Paper IV, which showed a number of proteins that were altered in their relative abundance using membrane and soluble isolation techniques. Further analyses of these identified changes were carried out and replicated in Paper V, which revealed and confirmed the changes in protein expression and abundance of proteins earlier identified in Papers I and II. Changes were identified in V144D mutations, as well as C133W and C133Y mutations. All of which are implicated to be casual of HSN-I. Lipid droplets and alterations of lipid metabolism are hallmarks of a variety autosomal dominant neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. Paper VI, revealed significant increases in the presence of lipid droplets in HSN-I patient-derived lymphoblasts, indicating a potential connection between lipid droplet formation and the molecular mechanisms of HSN-I. In conclusion, this study has shown alteration in mitochondrial and ER protein profiles in patient-derived lymphoblasts and in transfected neuronal cells expressing the mutations V144D, C133W and C133Y. This investigation has contributed to the field by identifying protein alterations which has yielded a more detailed and in-depth analysis of the cellular and molecular mechanisms involved in HSN-I. iv | Page THESIS STRUCTURE The work presented in this thesis provides an investigation into mitochondrial and endoplasmic reticulum proteome changes caused by mutations in the SPTLC1 gene. These investigations are provided as a series of six papers (listed below). These papers are either published (Paper I, II, III, IV & VI), or currently submitted to journals for peer-review (Paper V), and adverted to in the thesis text by their Roman numerals. I. Stimpson, SE. Coorssen, JR. Myers, SJ. Optimal isolation of mitochondria for proteomic analyses. Analytical Biochemistry: Methods in Biological Sciences, 2015. doi:10.1016/j.ab.2015.01.005 II. Stimpson, SE. Coorssen, JR. Myers, SJ. Mitochondrial protein alterations in a familial peripheral neuropathy caused by mutations in the sphingolipid protein, SPTLC1. J Chem Biol, 2014. 8 (1):25-35. Doi: 10.1007/s12154-014-0125-x. III. Stimpson, SE. Lauto, A. Coorssen, JR. Myers, SJ. Isolation and identification of ER associated proteins with unique expression changes specific to the V144D SPTLC1 mutations in HSN-I. Biochem and Anal Biochem. 2016; 5 (1) IV. Stimpson, SE. Coorssen, JR. Myers, SJ. Proteome alterations associated with the V144D SPTLC1 mutation that causes Hereditary Sensory Neuropathy-I. Electronic J Biol, 2015; 11 (4): 176-186 V. Stimpson, SE. Coorssen, JR. Myers, SJ. Identifying unique protein alterations caused by SPTLC1 mutations in a transfected neuronal cell model. Proteomes. 2015 (Manuscript under Review). VI. Marshall, LL*. Stimpson, SE*, Coorssen, JR and Myers, SJ. Increased lipid droplet accumulation associated with a peripheral sensory neuropathy. J Chem Biol. 2014; 7(2):67-76. Doi: 10.1007 (* Co-first authors). v | Page TABLE OF CONTENTS Abbreviated list of contents………………………………………..……………………… vi Comprehensive list of contents………………….……………………..………………... vii List of Figures………….………………………………………..……………..…….….. viii List of Tables ...…………………..…………………………..………………….............viii Acknowledgements..................................................................................................ix List of Abbreviations………………..……..................................................................x vi | Page TABLE OF CONTENTS 1.1 Hereditary Sensory Neuropathies ............................................................................................... 1 1.1.1 What are hereditary sensory neuropathies? ...................................................................... 1 1.1.2 Clinical features of HSN-I ...................................................................................................... 5 1.1.3 Pathological features of HSN-I ............................................................................................. 5 1.1.4 Genetics of HSN-I .................................................................................................................. 6 1.2 Intracellular Lipid Functions and Interactions ............................................................................ 7 1.2.1 The role of lipids in biological membranes ......................................................................... 7 1.2.2 Interactions of lipids with intracellular proteins and organelles ....................................... 9 1.2.3 Sphingolipids, their role in normal cellular homeostasis and in the neuronal cell ...... 11 1.3 Serine Palmitoyltransferase ....................................................................................................... 13 1.3.1 The structure and regulation of SPT and its subunits ..................................................... 13 1.3.2 The role of the SPTLC1 protein in neurodegenerative disease .................................... 14 1.4 Protein Functions and Interactions ........................................................................................... 17 1.4.1 Altered protein expression and the disease state ........................................................... 17 1.5 Mitochondria in neurodegenerative diseases .......................................................................... 19 1.5.1 Mitochondrial Dynamics ...................................................................................................... 19 1.5.2 Mitochondrial fusion and fission ......................................................................................... 20 1.5.3 Mitochondrial changes in inherited peripheral neuropathies ......................................... 27 1.5.4 Examples of Mitochondrial changes in inherited peripheral .......................................... 29 Neuropathies ................................................................................................................................... 29 1.5.5 Novel link to Mitochondria in HSN-I ................................................................................... 32 1.6 The Role of ER in neurodegenerative diseases ..................................................................... 33 1.6.1 Protein processing in the ER .............................................................................................. 33 1.6.2 UPR: Unfolded protein response pathway ....................................................................... 37 1.7 Mitochondria-Associated Membranes ...................................................................................... 41 1.7.1 MAM Calcium Regulation .................................................................................................... 41 1.7.2 Autophagy formation at MAMs ........................................................................................... 42 1.7.3 Lipid transportation via MAMs ...........................................................................................
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