Role of SPHK2S1P signalling in regulating mitochondrial function in the MPTP induced mouse model of parkinsons disease and in the MPP treated MN9D cells

ROLE OF SPHK2/S1P SIGNALLING IN REGULATING MITOCHONDRIAL FUNCTION IN THE MPTP – INDUCED MOUSE MODEL OF PARKINSON’S DISEASE AND IN THE MPP+-TREATED MN9D CELLS MEENALOCHANI SIVASUBRAMANIAN A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF ANATOMY YONG LOO LIN SCHOOL OF MEDICINE NATIONAL UNIVERSITY OF SINGAPORE 2014 DECLARATION I hereby declare that this thesis is my original work and it has been written by me in its entirety I have duly acknowledged all the sources of information which have been used in the thesis This thesis has also not been submitted for any degrees in any university previously Name -: Meenalochani Sivasubramanian Date -: 9th February, 2014 I ACKNOWLEDGEMENTS This thesis would have remained a dream had it not been for my supervisor Associate Professor Tay Sam Wah Samuel, Department of Anatomy, National University of Singapore because of whom my graduate experience has been one that I will cherish forever I would like to express my sincere and deepest gratitude to him for his valuable guidance, erudite inputs and unfailing encouragement I received throughout the course of my study I cannot say thank you enough for his tremendous support and help I have always felt motivated and encouraged every time I meet him I have been extremely privileged to have been his student I am extremely indebted and grateful to Associate Professor Thameem S Dheen, Department of Anatomy, National University of Singapore, for his immense help throughout my course of study His scientific critiques have helped me to a great extent in my research for which, I am extremely thankful His help has been crucial in the completion of my thesis I am extremely thankful and grateful to Professor Charanjit Kaur for her encouragement and moral support throughout my candidature She has been a pillar of strength and a source of inspiration I would also like to thank my Thesis Advisory Committee members, Associate Professor Ng Yee Kong and Associate Professor Liang Fengyi for their valuable suggestions and guidance during the course of my study I would like to express my heartfelt gratitude to Professor Bay Boon Huat, Head of the Department of Anatomy, who gave me an opportunity to pursue my graduate studies in the Department II I would like to thank Ms Ng Geok Lan, Ms.Yong Eng Siang and Ms Chan Yee Gek for their valuable technical assistance in the labs I would also like extend my thanks to Mr Yick Tuck Yong, Ms Carolyne, Ms Violet Teo and Ms Diljit Kour, for their help in providing administrative assistance I must thank my lab mates Mrs Nandhini kanagaraj and Ms Ooi Yin Yin for their friendly support throughput the course of my study I owe my deepest gratitude to my parents for their eternal love, support and understanding of my goals and aspirations A special thank to my younger brotherwho gave me all the support that he can for me to write this thesis I feel a deep sense of gratitude for my inlaws for their constant support and patience throughout the course of this study I would like to express my heartfelt gratitude to my brotherinlaw and my sisterinlaw who has given us immense support in all possible means just for me to complete this course If not for the infallible love and support from my husband this endeavour would not have been possible His patience and sacrifice will remain an inspiration for the rest of my life I would like to thank my children Sonakshi and El Morya for being co operative and allowing me to write my thesis Last but not the least I would like to express my gratitude to the almighty for the divine blessings and grace upon my life III Dedicated to my beloved children Sonakshi and El Morya IV PUBLICATIONS Various parts of this study have been presented, submitted for publication or under preparation for publication Publications  Sivasubramanian Meenalochani, Nandhini Kanagaraj, S Thameem Dheen, Samuel, Sam Wah Tay* Possible role of sphingosine kinase 2/S1P signaling in promoting mitochondrial function in the MPTPinduced mouse model of Parkinson’s disease and in MPP+- treated MN9D cells (Manuscript in Press) in Neuroscience  Sivasubramanian Meenalochani, S Thameem Dheen, Samuel, Sam Wah Tay* Role of sphingosine kinase and sphingosine kinase in apoptotic cell death evoked by 1-Methyl-4-Phenylpyridinium (MPP+) in the MN9D cells in vitro Manuscript in preparation Conference Presentations  SNA SYMPOSIUM 2014……………………………… (Poster presentation) Sphingosine kinase and Sphingosine-1-phosphate signalling in mitochondrial dysfunction in the dopaminergic neurons  SNA SYMPOSIUM 2013……………………………… (Poster presentation) Dysregulated sphingosine kinase expression leads to the activation of apoptotic cascade in the MPTP-induced mouse model of Parkinson’s disease V  Experimental Biology 2013 Meeting in San Diego, CA Alteration in the sphingolipid metabolism leads to activation of the apoptotic cascade in the MPTP induced mouse model of Parkinson’s disease  Experimental Biology 2012 Meeting in Boston, MA Dysregulated Sphk1, Sphk2 and their receptors in the brain of MPTPinduced mouse model of Parkinson’s disease VI TABLE OF CONTENTS DECLARATION I ACKNOWLEDGEMENTS II PUBLICATIONS V SUMMARY XIX LIST OF TABLES XXIV TEXT FIGURES XXIV ABBREVIATIONS XXV CHAPTER INTRODUCTION 1.1 Parkinson’s disease 1.2 Epidemiology of PD 1.3 PD - Signs and Symptoms 1.4 Diagnosis 1.5 Existing treatments for PD 1.6 Pathological hallmarks of PD 1.7 Potential risk factors in PD 1.7.1 Aging- The cardinal factor 1.7.2 Environmental factors 1.7.3 Genetic factors in PD VII 1.7.3.1α-Synuclein (SNCA) 1.7.3.2 Parkin 1.7.3.3 UCH-L1 10 1.7.3.4 PINK1 11 1.7.3.5 DJ-1 11 1.7.3.6 LRRK2 12 1.7.3.7 ATP13A2 12 1.7.3.8 Genes likely to have a role in PD 13 1.8 Animal models of PD 13 1.8.1 6-Hydroxy Dopamine (6-OHDA) model 13 1.8.2 Systemic rotenone model 14 1.8.2.1 Paraquat and Maneb 14 1.8.3 MPTP model of PD 15 1.8.3.1 Mechanism of MPTP action 15 1.9 Possible Pathways involved in the pathogenesis of PD 17 1.9.1 Inflammation 17 1.9.2 Excitotoxicity 18 1.9.3 Impairment of the Ubiquitin-Proteasome System (UPS) 18 1.9.4 Oxidative stress in PD 19 VIII 1.9.5 Mitochondrial dysfunction in PD 20 1.10 Lipids in the Central Nervous System (CNS) 21 1.10.1 Sphingolipids - The Enigmatic Class of Lipids 22 1.10.2 Synthesis and metabolism of sphingolipids 22 1.10.3 Sphingosine kinases 23 1.10.3.1 Sphingosine kinase 1(SphK1) 23 1.10.3.2 Sphingosine kinase 2(SphK2) 24 1.10.4 Localization of Sphk1 and Sphk2 24 1.10.4.1 Synthesis of Sphingosine-1-phosphate 25 1.10.4.2 Activation of Sphingosine kinases 25 1.10.5 S1P Receptors 27 1.10.5.1 Sphingosine kinases and S1P in the brain 28 1.10.5.2 S1P receptors in the CNS 29 1.10.5.3 Role of Sphingosine kinases and S1P in neurodegeneration 30 1.11 Aims of the present study 31 1.11.1 To establish an acute MPTP-induced PD mouse model 31 1.11.2 To validate the animal model by investigating the degeneration of dopaminergic neurons in the substantia nigra 32 1.11.3 To 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Possible role of sphingosine kinase 2/S1P signaling in promoting mitochondrial function in the MPTPinduced mouse model of Parkinson’s disease and in MPP+ - treated MN9D cells (Manuscript in Press) in. .. changes observed in the MPTP- induced mouse model of Parkinson’s disease 102 4.2 Expression pattern of TH and DAT in the MPTP induced mouse model 103 4.3 Proinflammatory cytokine TNFα was... implicated in PD pathogenesis, the expression pattern of TNFα and iNOS in the SNc of the MPTP- induced mouse model was analysed It was observed that there was an increase in the levels of XX TNF and iNOS