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New Insight Into Mechanisms of Transcellular Propagation of Tau and Α-Synuclein in Neurodegenerative Diseases Recent Publications in This Series

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New Insight Into Mechanisms of Transcellular Propagation of Tau and Α-Synuclein in Neurodegenerative Diseases Recent Publications in This Series XU YAN Recent Publications in this Series 77/2016 Aino Salonsalmi Alcohol Drinking, Health-Related Functioning and Work Disability 78/2016 Heini Wennman Diseases Neurodegenerative in of Tau and α-Synuclein of Transcellular Propagation Mechanisms into New Insight Physical Activity, Sleep and Cardiovascular Diseases: Person-oriented and Longitudinal Perspectives 79/2016 Andres Lõhmus DISSERTATIONES SCHOLAE DOCTORALIS AD SANITATEM INVESTIGANDAM Helper Component-Proteinase and Coat Protein are Involved in the Molecular Processes of UNIVERSITATIS HELSINKIENSIS 7/2017 Potato Virus A Translation and Replication 80/2016 Li Ma Brain Immune Gene Network in Inbred Mouse Models of Anxiety- and Sociability-related Neuropsychiatric Disorders 81/2016 Finny S. Varghese Cracking the Code of Chikungunya Virus: Inhibitors as Tools to Explore Alphavirus Biology 82/2016 Vera Shirokova Transcription Factor Foxi3 in Hair Follicle Development and Homeostasis XU YAN 83/2016 Daria Bulanova Novel Genetic Determinants of Breast Cancer Progression New Insight into Mechanisms of Transcellular 84/2016 Hugh Chapman The hERG1 (KV11.1) Potassium Channel: Its Modulation and the Functional Characterisation of Propagation of Tau and α-Synuclein in Genetic Variants Neurodegenerative Diseases 85/2016 Katja Rosti Expression and Characterization of Neuronal Membrane Receptor Proteins 86/2016 Irepan Salvador-Martínez Estimating Complexity and Adaptation in the Embryo: A Statistical Developmental Biology Approach 87/2016 Vigneshwari Subramanian Field-based Proteochemometric Models Derived from 3D Protein Structures: A Novel Approach to Visualize Affinity and Selectivity Features 88/2016 Anita Lampinen Signalling and Expression of the Ang-Tie Pathway in Tumor Vasculature 1/2017 Essi Havula Transcriptional Control of Dietary Sugar Metabolism and Homeostasis by Mondo-Mlx Transcription Factors 2/2017 Satu Massinen Specific Reading Disorder: Cellular and Neurodevelopmental Functions of Susceptibility Genes 3/2017 Margarita Andreevskaya Ecological Fitness and Interspecies Interactions of Food-Spoilage-Associated Lactic Acid Bacteria: Insights from the Genome Analyses and Transcriptome Profiles 4/2017 Mikko Siurala Improving Adenovirus-Based Immunotherapies for Treatment of Solid Tumors 5/2017 Inken Körber NEUROSCIENCE CENTER AND Microglial Dysfunction in Cstb-/- Mice, a Model for the Neurodegenerative DEPARTMENT OF BIOSCIENCES Disorder Progressive Myoclonus Epilepsy of Unverricht-Lundborg Type, EPM1 FACULTY OF BIOLOGICAL AND ENVIRONMENTAL SCIENCES 6/2017 Shrikanth Kulashekhar DOCTORAL PROGRAMME BRAIN & MIND The Role of Cortical Oscillations in the Estimation and Maintenance of UNIVERSITY OF HELSINKI Sensory and Duration Information in Working Memory 7/2017 Helsinki 2017 ISSN 2342-3161 ISBN 978-951-51-2865-2 Neuroscience Center And Department of Biosciences Faculty of Biological and Environmental Sciences Doctoral programme in Brain & Mind University of Helsinki NEW INSIGHT INTO MECHANISMS OF TRANSCELLULAR PROPAGATION OF TAU AND D-SYNUCLEIN IN NEURODEGENERATIVE DISEASES Xu Yan ACADEMIC DISSERTATION To be presented, with the permission of the Faculty of Biological and Environmental Sciences, University of Helsinki, for public examination in lecture room B105, Cultivator II, Viikki, on 10th February 2017, at 12 noon. Helsinki 2017 Supervisor Docent Henri Huttunen, PhD Neuroscience Center, University of Helsinki, Finland Thesis committee Docent Mikko Airavaara, PhD Institute of Biotechnology, University of Helsinki, Finland Docent Tomi Rantamäki, PhD, Department of Biosciences, University of Helsinki, Finland Pre-examiners Docent Mikko Airavaara, PhD Institute of Biotechnology, University of Helsinki, Finland Docent Katja Kanninen, PhD, Institute for Molecular Sciences, University of Eastern Finland, Finland Opponent Assistant Professor Kelvin C Luk, PhD Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, U.S.A. Custos Professor Juha Voipio, PhD Department of Biosciences, University of Helsinki, Finland Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis ISSN 2342-3161 (print) ISSN 2342-317X (online) ISBN 978-951-51-2865-2 (paperback) ISBN 978-951-51-2866-9 (PDF) Unigrafia and Hansaprint Helsinki 2017 II TABLE OF CONTENTS List Of Original Publications .................................................................................................. V Abbreviations ......................................................................................................................... VI Abstract ................................................................................................................................ VIII 1 Introduction .......................................................................................................................... 1 2 Review of literature ............................................................................................................. 3 2.1 Protein misfolding and aggregation ............................................................................ 3 2.2 α-synuclein ..................................................................................................................... 5 2.2.1 Structure and biological functions ........................................................................ 5 2.2.2 α-synuclein aggregation ....................................................................................... 7 2.2.3 Clearance of aggregation .................................................................................... 10 2.2.4 α-synuclein toxic species .................................................................................... 11 2.2.5 Prolyl oligopeptidase .......................................................................................... 12 2.3 Tau ............................................................................................................................ 13 2.3.1 Structure and biological functions ...................................................................... 13 2.3.2 Phosphorylation .................................................................................................. 14 2.3.3 Kinases and phosphatases .................................................................................. 15 2.3.4 Other post-translational modifications ............................................................... 16 2.3.5 Tau aggregation .................................................................................................. 17 2.3.6 Genetic risk factors of Alzheimer’s disease ....................................................... 20 2.3.7 Tau ubiquitination and clearance ....................................................................... 23 2.3.8 Toxic species of tau ............................................................................................ 24 2.3.9 Interconnection between aSyn and tau ............................................................... 25 2.3.10 Therapeutic strategies against tauopathies and synucleinopathies ..................... 27 2.4 Misfolded protein propagation in pathological conditions ..................................... 28 2.4.1 Prion-like seeding ............................................................................................... 29 2.4.2 Cell-to-cell transmission of α-synuclein and tau ................................................ 32 2.4.3 Spread of pathology ............................................................................................ 37 2.4.4 The spread of pathology- what is missing from the story? ................................. 38 3 Aims of the study ................................................................................................................ 40 4 Materials and methods ...................................................................................................... 41 4.1 Plasmid constructs and recombinant proteins ......................................................... 41 4.2 Chemicals .................................................................................................................... 41 4.3 Antibodies .................................................................................................................... 42 4.4 Cell culture and transfections .................................................................................... 42 4.5 Protein-fragment complementation assay ................................................................ 42 4.5.1 Tau and aSyn secretion assay ............................................................................. 43 4.5.2 Assessment of tau and aSyn uptake .................................................................... 43 4.6 Electrophoretic techniques ........................................................................................ 43 4.6.1 Western blotting ................................................................................................. 43 4.6.2 Native polyacrylamide gel electrophoresis......................................................... 44 4.7 Fractionation techniques ............................................................................................ 44 4.7.1 Protein fractionation ........................................................................................... 44 4.7.2 Media fractionation ............................................................................................ 44 4.8 Protein crosslinking ...................................................................................................
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