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The Effects of Alpha-Synuclein Gain-Of-Function on Synaptic Plasticity

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The Effects of Alpha-Synuclein Gain-Of-Function on Synaptic Plasticity The effects of alpha-synuclein gain-of-function on synaptic plasticity Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften vorgelegt beim Fachbereich Biowissenschaften der Johann Wolfgang Goethe-Universität in Frankfurt am Main von Nadine Brehm *01.12.1985 Wiesbaden Frankfurt 2015 (D 30) vom Fachbereich Biowissenschaften der Johann Wolfgang Goethe-Universität als Dissertation angenommen. Dekan: Prof. Dr. Meike Piepenbring Gutachter: Prof. Dr. A. Starzinski-Powitz Prof. Dr. G. Auburger Datum der Disputation: 16.09.2015 b | Page Scientific publications and presentations from this thesis Publications Brehm N, Bez F, Carlsson T, Kern B, Gispert S, Auburger G§, Cenci MA§ (2014) „A genetic mouse model of Parkinson’s disease shows involuntary movements and increased post-synaptic sensitivity to apomorphine.”Mol Neurobiol. Oct 12. [Epub ahead of print] Gispert S§, Brehm N§, Weil J, Seidel K, Rüb U, Kern B, Walter M, Roeper J, Auburger G (2014) „Potentiation of neurotoxicity in double mutant mice with Pink1 ablation and A53T-SNCA overexpression.” Hum Mol Genet, 24(4):1061-76. § shared first author Poster Presentations N. Brehm, F. Bez, S. Gispert, M. A. Cenci, G. Auburger (2014) „Striatal post-synaptic supersensitivity in a genetic mouse model of Parkinson’s disease.” Parkinson’s Disease: Genetics, Mechanisms and Therapeutics (Keystone Symposium, Colora- do) Nadine Brehm, Alexander Kurz, Suzana Gispert, Georg Auburger (2013) „Identification of molecular markers for early pathology and progression of Parkinson`s dis- ease.” AD/PD Conference, Florence N. Brehm, A. Kurz, S. Gispert, G. Auburger (2013) „Homer1 and Nurr77 are possible biomarkers for early nigrostriatal pathology in Parkinson’s disease (PD).” New Frontiers in Neurodegenerative Disease Research (Santa Fe, New Mexico) Oral Presentation “Mouse Models of Parkinson’s Disease” (18.11.2014) Educational program of IMPRS “Modern Topics in neuroscience” Max-Planck Institute for Brain Research, Frankfurt „A genetic mouse model of Parkinson’s disease shows involuntary movements and increased post-synaptic sensitivity to apomorphine.” (11.9.2014) 52. Wissenschaftliche Tagung der Gesellschaft für Versuchstierkunde in Frankfurt am Main c | Page „A genetic mouse model of Parkinson’s disease shows involuntary movements and increased post-synaptic sensitivity to apomorphine.” (10.07.2014) Young Investigators Colloquium, Neuroscience Center Frankfurt am Main “Mouse Models of Parkinson’s Disease” (11.11.2013) Educational program of IMPRS “Modern Topics in neuroscience” Max-Plack Institut for Brain Research, Frankfurt Scientific publications and presentations outside this thesis Publications Gispert S, Kurz A, Brehm N, Rau K, Walter M, Riess O, Auburger G (2014) “Complexin-1 and Foxp1 Expression Changes Are Novel Brain Effects of Alpha-Synuclein Pa- thology.” Mol Neurobiol. Aug 12. [Epub ahead of print] Dominguez-Bautista JA, Klinkenberg M, Brehm N, Subramaniam M, Kern B, Roeper J, Au- burger G, Jendrach M (2015) „Loss of lysosome-associated membrane protein 3 (LAMP3) enhances cellular vulnerability against proteasomal inhibition.” European Journal of Cell Biology. Jan 30 [Epub ahead of print] Manuscripts in Revision or Submission Mai S, Brehm N, Auburger G, Bereiter-Hahn J, Jendrach M: „Age-induced dysfunction of the autophago-lysosomal pathway in human endothelial cells“ In revision at Journal of Biological Chemistry N. Brehm§, K. Rau§, A. Kurz, S. Gispert, G. Auburger: „Age-related changes of 14-3-3 isoforms in midbrain of A53T-SNCA overexpressing mice” § shared first author In revision at Journal of Molecular Neuroscience d | Page Lahut S§, Gispert S§, Ömür Ö, Depboylu C, Seidel K, Domínguez-Bautista J, Brehm N, Tireli H, Hackmann K, Pirkevi C, Leube B, Ries V, Reim K, Brose N, Den Dunnen W, Johnson M, Wolf Z, Schindewolf M, Frangakis AS, Schröck E, Steinmetz H, Jendrach M, Rüb U, Oertel W, Ba Auburger G.: şak AN, “Blood biomarkers of risk for synucleinopathy, a variant of Parkinson’s disease” In submission at Proc. Natl. Acad. Sci. USA. e | Page Table of Contents 1. INTRODUCTION ............................................................................................................................................................... 1 1.1 PARKINSON’S DISEASE ....................................................................................................................................................................... 1 1.1.1 Symptoms and Diagnosis ................................................................................................................................................... 1 1.2 PHYSIOLOGY AND NEUROPATHOLOGY OF PARKINSON’S DISEASE ............................................................................................. 3 1.2.1 Anatomy and Physiology of the Basal Ganglia and Dopamine Networks ....................................................... 3 1.2.1.1 The Direct and Indirect Pathway .................................................................................................................................................. 5 1.2.1.2 The Role of Dopamine in the Basal Ganglia .............................................................................................................................. 6 1.2.2 Lewy Body Pathology........................................................................................................................................................... 7 1.2.3 Protein Degradation in Healthy Aging and Parkinson`s Disease .................................................................... 10 1.3 GENETICS OF PARKINSON`S DISEASE ........................................................................................................................................... 10 1.3.1 Genes and Loci Associated with Parkinson’s Disease ........................................................................................... 11 1.3.2 Autosomal Dominant Forms of PD .............................................................................................................................. 12 1.3.2.1 Alpha-Synuclein (Park1/4) ........................................................................................................................................................... 13 1.3.2.1.1 Protein Family and Function of Alpha-Synuclein ............................................................................................... 14 1.3.3 Autosomal recessive forms of PD ................................................................................................................................. 18 1.3.3.1 PTEN-induced Kinase 1 (Park6) ................................................................................................................................................. 18 1.3.3.1.1 PINK1 Function and Role for Parkinson’s Disease ............................................................................................. 19 1.4 THERAPY OF PARKINSON’S DISEASE ............................................................................................................................................ 21 1.4.1 Therapeutic Side Effects - Levodopa Induced Dyskinesia................................................................................... 23 1.4.1.1 Molecular Basis of Levodopa Induced Dyskinesia ............................................................................................................. 26 1.5 MOUSE MODELS OF PARKINSON’S DISEASE ................................................................................................................................ 28 1.5.1 Genetically Engineered Mouse Models of PD ........................................................................................................... 28 1.5.1.1 The A53T-SNCA Overexpressing Mouse Model .................................................................................................................. 29 1.5.1.2 The Pink1KO Mouse Model ........................................................................................................................................................... 29 1.5.1.3 The A53T-SNCA + Pink1KO Mouse Model ............................................................................................................................. 30 1.5.2 The 6-OHDA Lesioned Mouse Model ........................................................................................................................... 30 1.6 AIM OF THE THESIS ......................................................................................................................................................................... 32 2. MATERIAL AND METHODS ........................................................................................................................................ 33 2.1 MATERIAL ..................................................................................................................................................................................... 33 2.1.1 General Laboratory Equipment .................................................................................................................................... 33 2.1.2 Behavioral Analysis and Perfusion .............................................................................................................................. 34 2.1.2.1 Instruments .........................................................................................................................................................................................
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