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Modelling Alpha-Synuclein-Based Parkinson's Disease and Studies Institute of Biotechnology HiLIFE & Division of Pharmacology and Pharmacotherapy Faculty of Pharmacy & Doctoral Programme in Drug Research Doctoral School in Health Sciences University of Helsinki MODELLING ALPHA-SYNUCLEIN-BASED PARKINSON’S DISEASE AND STUDIES WITH CDNF Katrina Albert ACADEMIC DISSERTATION Doctoral dissertation, to be presented for public examination with the permission of the Faculty of Pharmacy of the University of Helsinki, in hall 1041, Biokeskus 2, Viikinkaari 5, on the 17th of May, 2019 at 12 o’clock. Supervisors Docent Mikko Airavaara, PhD Institute of Biotechnology, HiLIFE University of Helsinki Helsinki, Finland Docent Merja H. Voutilainen, PhD Institute of Biotechnology, HiLIFE University of Helsinki Helsinki, Finland Professor Mart Saarma, PhD Institute of Biotechnology, HiLIFE University of Helsinki Helsinki, Finland Professor Raimo K. Tuominen, MD, PhD Faculty of Pharmacy University of Helsinki Helsinki, Finland Reviewers Assistant Professor Grzegorz Kreiner, PhD Institute of Pharmacology Polish Academy of Sciences Krakow, Poland Docent Šárka Lehtonen, PhD A.I.Virtanen Institute for Molecular Sciences University of Eastern Finland Kuopio, Finland Opponent Professor Maria Grazia Spillantini, FMedSci FRS Department of Clinical Neurosciences University of Cambridge Cambridge, United Kingdom Custos Professor Raimo K. Tuominen, MD, PhD Faculty of Pharmacy University of Helsinki Helsinki, Finland ISBN 978-951-51-5217-6 (paperback) ISBN 978-951-51-5218-3 (PDF) ISSN 2342-3161 (print) ISSN 2342-317X (online) Helsinki 2019 To my Dad CONTENTS Abstract ......................................................................................... iv Abbreviations ................................................................................ vi Original Publications .................................................................. viii 1 Introduction .............................................................................. 1 2 Review of the Literature .......................................................... 2 2.1 Parkinson’s disease ................................................................... 2 2.1.1 Dopamine neuron degeneration in Parkinson’s disease ....................................... 2 2.1.2 Other neurons involved in Parkinson’s disease ..................................................... 5 2.1.3 Current treatments in Parkinson’s disease............................................................. 5 2.1.4 Progress in Parkinson’s disease-modifying therapy .............................................. 7 2.1.5 Genetic forms of Parkinson’s disease .................................................................... 8 2.2 Alpha-synuclein ........................................................................ 9 2.2.1 Alpha-synuclein function and knockout models ....................................................9 2.2.2 Alpha-synuclein and dopamine ............................................................................ 11 2.2.3 Alpha-synuclein structure ..................................................................................... 12 2.2.4 Alpha-synuclein in neurodegenerative diseases .................................................. 15 2.2.5 Alpha-synuclein and protein degradation ............................................................ 17 2.2.6 Alpha-synuclein as a biomarker and drug target ................................................. 18 2.3 Animal models of Parkinson’s disease .................................... 20 2.3.1 Toxin models ......................................................................................................... 20 2.3.2 Genetic models ...................................................................................................... 22 2.3.3 Alpha-synuclein viral overexpression models ......................................................23 2.3.4 Preformed alpha-synuclein fibrils model ............................................................ 28 2.4 Cerebral dopamine neurotrophic factor (CDNF) ..................... 30 2.4.1 CDNF and related factor MANF .......................................................................... 30 2.4.2 CDNF in Parkinson’s disease ................................................................................ 31 3 Aims ....................................................................................... 34 4 Materials and Methods ...........................................................35 4.1 Methodological considerations ............................................... 35 4.1.1 Animal strains ........................................................................................................ 35 4.1.2 Intracranial microinjections................................................................................. 36 4.1.3 Positive and negative controls in disease modeling ............................................. 37 4.2 Preformed alpha-synuclein fibrils selected methods ............... 39 4.2.1 Animals .................................................................................................................. 39 4.2.2 Preparation, sonication, and injection of fibrils.................................................. 39 4.2.3 Counting of pS129-positive alpha-synuclein inclusions ...................................... 41 5 Results .................................................................................... 42 5.1 Effects of AAV-alpha-synuclein injected above the substantia nigra of rats (II) ................................................................................ 42 5.2 AAV downregulates TH in the substantia nigra pars compacta after injection above the substantia nigra (II) ................................... 42 5.3 Injection of alpha-synuclein preformed fibrils results in widespread phosphorylated alpha-synuclein in anatomically connected areas (III) ......................................................................... 43 5.4 Effects of alpha-synuclein preformed fibrils and treatment with CDNF in mice and rats (III) ............................................................... 45 5.5 Effects of a single injection of CDNF to the substantia nigra or in combination to the striatum in the 6-OHDA model in rats ................ 48 ii 5.6 Diffusion and localization of CDNF after injection to the rat substantia nigra (IV) ......................................................................... 50 5.7 Behaviour and histological outcomes of lactacystin-injected mice (V) .............................................................................................55 6 Discussion ............................................................................... 57 6.1 AAV-alpha-synuclein model (II) ............................................... 57 6.2 Preformed alpha-synuclein fibrils model and cdnf (III) .......... 58 6.3 Effects of CDNF injected to the substantia nigra in 6-OHDA and naïve rats (IV) ................................................................................... 60 6.4 Comparison of Parkinson’s disease animal models .................. 61 7 Conclusions ............................................................................ 63 8 Acknowledgements ................................................................ 64 9 References .............................................................................. 66 iii ABSTRACT The neurodegenerative disorder Parkinson’s disease is often diagnosed when motor symptoms appear, at which time approximately 30% of the substantia nigra dopamine neurons have already died. The majority of disease cases are idiopathic, and there are currently no disease-modifying therapies. Since the specific molecular mechanisms underlying Parkinson’s disease are still unknown, bringing treatments to the clinic has been difficult. However, in searching for both the underlying aetiology of the disease and a cure for it, animal models have brought valuable insights. Parkinson’s disease animal models have been developed using toxins to cause nigrostriatal degeneration, genetic manipulation, and through the use of alpha-synuclein. Alpha- synuclein is a 14 kDa protein found abundantly in the central nervous system of vertebrates. Its importance for Parkinson’s disease was clarified when it was discovered that mutations in the gene led to an autosomal dominant disease form and that it is the majority protein in what is considered a pathological marker of the disease, Lewy bodies. With these discoveries, alpha-synuclein animal models became an important tool in Parkinson’s disease research. Cerebral dopamine neurotrophic factor (CDNF) is a highly conserved protein in vertebrates with neurotrophic-like properties. It has been shown to protect dopamine neurons in rodent toxin models of Parkinson’s disease and is currently in Phase I/II clinical trials for the disease. It has not been tested in alpha-synuclein animal models however, and therefore the aim of these studies was to model alpha-synuclein-based Parkinson’s disease in rodents and to test whether CDNF can intervene with alpha-synuclein aggregation and has therapeutic effects in these models. We generated two models that used alpha-synuclein specifically to attempt to model sporadic Parkinson’s disease in rodents and test CDNF on: adeno- associated virus (AAV) and preformed fibrils. We used an AAV to overexpress human wild-type alpha-synuclein in rats by injecting the virus above the substantia nigra, with the end goal to test CDNF. We successfully modeled the nigrostriatal dopamine loss
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