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Glial Changes in Atypical Parkinsonian Syndromes

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Glial Changes in Atypical Parkinsonian Syndromes Glial changes in atypical parkinsonian syndromes Yun Ju Christine Song A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy August 2008 University of New South Wales Department of Anatomy Supervisors: Professor Glenda M Halliday Dr Yue Huang 1 Acknowledgements It feels surreal realising that I have come to the end of this unbelievably challenging but rewarding journey. I could not have come this far without the amazing help and guidance from so many important people and I am deeply grateful to everybody who has contributed to the steps I have taken in completing this journey. To my supervisor Glenda Halliday, thank you so much for all your encouragement and guidance. I have continuously learnt so much from you and there have been countless times where I have been in constant awe of your drive, passion and knowledge about these movement disorders. Thank you for all your teachings and enthusiasm for my work, and believing that I could achieve this. I could not have come this far without such a first-class supervisor. To my co-supervisor Yue Huang, your passion for MSA pushed me to search for more and you always helped me to think from a different perspective. I have learnt many things from you and I thank you for your support. My dearest friend and lab manager Heather, your meticulous training and perfectionism in the lab and has helped me to achieve this much. Thank you for your technical guidance, I have the deepest regard for you, both as a teacher and friend. Karen, my second lab manager, thanks for being so helpful and supportive right to the very end. You have become such a dear friend and I appreciate all that you have done for me. Heidi, I owe so much to you, thank you for your patience and turning my images into artwork. I thank you Farid, Claire and Emma for all your words of wisdom and Fabs for all your technical support. To my collaborators Professor Poul Henning Jensen and Dr Paul Lockhart, your enthusiasm and interest in these glial proteins is what started this project and I thank you for your guidance and encouragement. I was so fortunate to do part of my PhD at the Queen Square Brain Bank. I owe so much to Professor Tamas 2 Revesz who taught me the beauty of neuropathology. Spending endless hours on the microscope with you and your encouragement and teachings has contributed so much to this journey, thank you. Dr Janice Holton, thank you for your ongoing support and faith in me as a researcher. Thank you to my friend and supervisor Dr Tammaryn Lashley, you are an amazing super-woman that had the answer to everything! To my dearest friends at Queen Square, Sudi, Kate, Hil, Perdi, Dan and Idris, your friendships made my UK experience so much more rewarding. I will always cherish your love and care, thank you! I am so grateful for my dear friends Jo, Fran and Lol (fellow PhD buddy) who gave me hugs, smiles and cups of tea when needed most. My study room pals Daniel, Dave, Elias, Sarah, Jacob and Fatima who shared my rants and raves, I thank you all. To my support team Nancy, Jo, Narae, Julie, Danbi, Beks, Jen and Kristy, you girls have helped me maintain my sanity through the past years. Special thanks to Beks, Jen and Kristy for your amazing proof-reading skills and Nancy for being my special shoulder to cry on. I am so grateful for all your prayers and endless encouragement, and keeping me focused on the unseen, your friendships have been invaluable to this journey. My family have put up with so much throughout this journey, I am so deeply grateful. To my mum and brother for believing in me, embracing my breakdowns and your constant prayers and words of comfort has helped me to persevere and continue in running the race. To Jamie, you have been so patient and understanding, I owe alot to you. Thank you for putting up with my tears and struggles, you helped me reach the finish line and I thank you dearly. To my Lord, you showed me that all things are possible through you. Thank you for your grace and guiding me till the very end. I give this and all glory to you. This doctorate was funded by the Australian Government, GlaxoSmithKline Australia and Parkinson’s NSW and a personal thank you to all the brain donors and the Australian Brain Donor Programs. 3 Abstract Idiopathic Parkinson’s disease (PD) and the atypical parkinsonian syndromes progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) have substantial overlap in clinical features, with parkinsonian and cerebellar phenotypes identified. Pathologically, reactive glial changes occur in overlapping pathways in these disorders. Recent findings that glia concentrate proteins associated with genetic forms of PD, suggest a more significant role for these cells in the pathogenesis of these disorders. This study is the first to comparatively assess glial abnormalities in PD, PSP and MSA. Cases were clinically and pathologically characterised to establish correlates to prominent glial changes. The three main types of glia (astrocytes, oligodendroglia and microglia) were characterised by morphological features and protein expression (using immunohistochemical techniques) for correlations with disease indices. Tissue features measured included subregional volumes, nigral cell loss, characteristic disease inclusions, and the densities of glia. Using these techniques, the parkin co-regulated gene protein was found to be a novel constituent protein in protoplasmic astrocytes, facilitating the assessment of glial subtypes. The data show that distinct glial abnormalities associate with each parkinsonian syndrome. The most marked differences were observed in the astrocytic 4 reaction in each disorder. In PD, protoplasmic astrocytes accumulated non- fibrillar -synuclein and degenerated over time, relating to a loss of levodopa responsiveness. In PSP, there was a marked protoplasmic astrogliosis (with these reactive glia strongly expressing parkin) that related to PSP-prominent clinical symptoms. In MSA, there was a marked fibrous astrogliosis and a loss of protoplasmic astrocytes in association with early changes in constituent myelin and oligodendroglial proteins. In contrast, similar microglial activation was observed across all disorders, with phagocytes concentrating in the substantia nigra, while non-phagocytic reactive microglia expressed parkin and associated with inclusion formation in each disorder. Overall, the glial reactions were considered to be either contributing to or ameliorating (neuroprotective) the neurodegenerative processes, and the timing of these reactions assessed with respect to indices of disease progression. The novel findings of this thesis show that glial abnormalities are prominent but distinct, and occur early in these parkinsonian syndromes. Suggestions on how these findings may translate into future therapeutic targets are given. 5 Table of Contents CHAPTER 1: INTRODUCTION............................................................... 22 1.1 Parkinson’s disease and atypical parkinsonian disorders .......... 22 1.1.1 Clinical features and diagnosis ....................................................... 22 1.1.2 Overlapping phenotypes in parkinsonian disorders ........................ 25 1.1.3 Genetics.......................................................................................... 27 1.1.4 Core pathologies differentiating Parkinson’s disease, progressive supranuclear palsy and multiple system atrophy ..................................... 31 1.1.5 Pathological staging and differences between clinical phenotypes. 35 1.1.5.1 Clinicopathological correlates: parkinsonian subtype........ 38 1.1.5.1 Clinicopathological correlates: cerebellar subtype ............ 41 1.1.6 Summary......................................................................................... 43 1.2 Cell specific protein changes in Parkinson’s disease and atypical parkinsonian disorders ......................................................................... 44 1.2.1 Abnormal protein expression in neurons......................................... 44 1.2.2 Abnormal protein expression in astrocytes ..................................... 48 1.2.3 Abnormal protein expression in oligodendroglia ............................. 49 1.2.4 Abnormal protein expression in microglia ....................................... 52 1.2.5 Summary......................................................................................... 53 1.3 Study objectives .............................................................................. 54 1.4 Major hypotheses ............................................................................ 55 CHAPTER 2: COMMON MATERIALS AND METHODS ........................ 56 2.1 Sources of tissue ............................................................................. 56 2.2 Case ascertainment and clinical information................................ 58 2.3 Standard preparation of brain tissue ............................................. 61 2.4 General immunohistochemical methods....................................... 62 2.4.1 Peroxidase immunohistochemistry (counterstained with 6 cresyl violet)............................................................................................. 62 2.4.2 Double-labelling immunofluorescence ............................................ 65 2.4.3 Combined peroxidase and immunofluorescence labelling .............. 66 CHAPTER 3: PATHOLOGICAL STAGING OF PROGRESSIVE SUPRANUCLEAR PALSY...................................................................... 68 3.1 Introduction.....................................................................................
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