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Thesis Reference Thesis Proteomic analysis of the substantia nigra in patients with Parkinson's disease LICKER, Virginie Abstract The specific cascade of biological events underlying substantia nigra neurodegeneration in Parkinson's disease (PD) remains elusive. To gain new insights into PD pathogenesis, we conducted some proteomic investigations of nigral autopsy tissues from patients with PD and controls. Our approach highlighted a set of proteins differentially expressed in PD. A majority of them such as CNDP2 or nebulette were novel candidates potentially engaged in PD pathological process. Overall, observed alterations tended to confirm well accepted concepts surrounding PD pathogenesis but also pointed out the involvement of less conventional ones such as ER stress, cytoskeleton or extracellular matrix impairments. This project provides further insights into PD pathogenesis and may ultimately help to delineate new therapeutic targets and biomarkers for the treatment and diagnosis of PD. Reference LICKER, Virginie. Proteomic analysis of the substantia nigra in patients with Parkinson's disease. Thèse de doctorat : Univ. Genève, 2013, no. Sc. 4532 URN : urn:nbn:ch:unige-333777 DOI : 10.13097/archive-ouverte/unige:33377 Available at: http://archive-ouverte.unige.ch/unige:33377 Disclaimer: layout of this document may differ from the published version. 1 / 1 UNIVERSITE DE GENEVE Département des Sciences des Protéines Humaines FACULTE DE MEDECINE Professeur P.R. Burkhard Section des Sciences Pharmaceutiques FACULTE DES SCIENCES Professeur D.F. Hochstrasser Proteomic Analysis of the Substantia Nigra in Patients with Parkinson’s Disease THESE Présentée à la Faculté des Sciences de l’Université de Genève pour obtenir le grade de Docteur ès Sciences, mention interdisciplinaire par Virginie Licker de Chermignon (VS) Thèse n°4532 Genève 2013 REMERCIEMENTS J’aimerais exprimer toute ma gratitude à ceux qui ont d’une façon ou d’une autre contribué à la réalisation de cette thèse. Aux membres du Jury, Prof. François Berger et Dr Christian Wider pour avoir accepté de lire et d’évaluer mon travail de thèse. Aux Prof. Pierre Burkhard et Denis Hochstrasser, directeur et co-directeur de thèse, qui m’ont permis d’évoluer au sein de leur laboratoire. Merci à Pierre de m’avoir encouragée à participer à des congrès internationaux de qualité, ainsi que pour la grande liberté laissée au cours de ces quatre ans qui m’a permis de gagner en indépendance scientifique. Au Prof. Jean-Charles Sanchez, pour m’avoir aidée à avancer et à me surpasser durant ces quatre années au travers de discussions scientifiques ainsi que par ses commentaires et relectures critiques. Son dynamisme, son enthousiasme et sa disponibilité auront été des moteurs essentiels. Au Dr Natacha Turck, pour son soutien autant scientifique que moral, pour ses commentaires pertinents quel que soit le sujet ainsi que pour sa « positive attitude ». Aux neuropathologues, les Dr. Alexander Lobrinus, Karim Burkhardt et Enikö Kovari dont la collaboration a permis la collecte des échantillons de substance noire. Un merci particulier à Enikö pour sa disponibilité, sa gentillesse et ses conseils, ainsi qu’à Maria Surini pour toute son aide sur la partie IHC. A Mélanie Côte, ma collègue, pour son aide et savoir-faire apportés tout au long de cette thèse. Ainsi que pour ses incroyables pâtisseries dont mes papilles se souviendront longtemps. A tous les membres du BPRG pour leur soutien au quotidien. A mes collègues doctorants, Natalia, Domitille, Didia, Xavier, Hui-Song, Florent, Francesco, ainsi qu’Alex (« &Co ») et Vanessa, ainsi qu’aux nouveaux venus Leire, Florian et Cindy. Merci pour votre soutien scientifique, votre solidarité mais aussi pour tous les bons moments passés ensemble, au labo ou en soirée, congrès et voyage! Qui aurait pu croire qu’un jour Harry, William, Prince Philip ou encore Victoria B s’inviteraient au BPRG… A Anne et Lisa, co-Queens of Sciences, avec qui j’ai beaucoup ri et partagé les petits soucis du quotidien comme les grandes questions existentielles. Ensemble nous avons appris à relativiser. Plutôt que de se préoccuper d’un projet voué à « s’effondrer » - les derniers WB, TMT ou IF ne fonctionnant pas, il est parfois préférable de se concentrer sur la subtile différence entre un Waikiki Orange et un Cajun Schrimp. Je n’arrive toujours pas à croire que j’ai réussi à vous faire participer à la course de l’Escalade, je l’écris pour la postérité. A mes princesses préférées Dany, Loyse, Auré, Vaness R, Jo, Steph, Olivia et la belle Amel. Merci pour tous ces précieux moments entre copines qui m’ont permis de déconnecter de mon doctorat. Merci de m’avoir écoutée et soutenue!! Le voyage à Barcelone fut une véritable bouffée d’oxygène durant ce dernier été « haletant ». A mes chers amis Louise, Lorric, Vaness P, Caro et David. Merci d’être toujours là depuis si longtemps. Un clin d’œil à deux de mes amis et prédécesseurs qui manquent cruellement au CMU, Lucie et Lorenzo! A Andrée, pour son inébranlable bonne humeur et gentillesse qui font de ma leçon de piano hebdomadaire un moment de détente incontournable depuis tant d’années. A Kim, pour m’avoir écoutée et soutenue à certains moments difficiles de ma thèse ainsi que pour être l’un des seuls à connaître mon sujet de thèse. A mes adorables manoriens Harris, Nat, Anais, Loichot, Béatrice, mais aussi Tatjana. Un remerciement particulier à Béa pour ne douter que rarement du bien-fondé de mes plaintes en tout genre et pour être toujours si bon public. A Nicolas, pour avoir mis un peu de Cassis, de Mouse, de Muse et de Mousse dans cette dernière phase d’écriture. A mes parents, mes grands-parents et à mon frère pour leurs encouragements et leur amour. Un merci tout particulier à Greg pour son irrésistible sens de l’humour et de la répartie: rien de tel qu’un bon fou rire pour oublier les soucis de la thèse... à toi de jouer maintenant, courage ! TABLE OF CONTENTS ABBREVIATIONS …………….…………………………….………………………………………………………………………. p. 3 ABSTRACT………..…..…………………………………………………………………………………………………………….... p. 5 RÉSUMÉ………..…..…………………………………………………………………………………………………………......... p. 7 CHAPTER I : GENERAL INTRODUCTION 1. Description of Parkinson’s disease…...………………………….…………………………………………... p. 11 1.1. Historical background.………………………………………………………………………………….. p. 11 1.1.1. PD in Ancient Times .………………………………………………………………………… p. 11 1.1.2. The first clinical definition of PD…………………………………………………………… p. 12 1.1.3. PD pathology ………………………………………………………………………..…………… p. 13 1.1.4. The miracle of levodopa …………………………..…………………………..…………… p. 14 1.2. Epidemiology: prevalence, incidence and socioeconomic aspects.………………. p. 15 1.3. Clinical description.…...……….....…………………………………………………………………… p. 16 1.3.1. Motor and non-motor symptoms………………………………………………………. p. 16 1.3.2. PD progression and rating scales……………………………………………………….. p. 17 1.4. Diagnosis.……………………………………………………………………………………………………… p. 19 1.5. Treatment…….………………………….…………………………………………………………………… p. 21 2. Etiopathogenesis of Parkinson’s disease…………………………………………………………………... p. 24 2.1. PD pathology ………………………………………………………………………………..……………… p. 23 2.1.1. The nigrostriatal pathway and the dopaminergic system…………………… p. 24 2.1.1.1. Anatomy and function of the basal ganglia…………………………….. p. 24 2.1.1.2. PD pathophysiology ………………………………………..…………………….. p. 25 2.1.1.3. Neuropathological hallmarks……………………………………….………… p. 27 2.1.2. Beyond the substantia nigra………………………………………..…………………….. p. 29 2.1.3. Braak staging of PD………………………………………..……………………….………….. p. 30 2.1.4. PD progression: a prion-like hypothesis? ……….…………………..…………….. p. 32 2.2. Risk factors and etiological hypotheses PD pathology …………………………….…… p. 34 2.2.1. Non-genetic risk factors……….……………………………………………..…………….. p. 34 2.2.2. Genetic risk factors……….…………………..……………………………………………….. p. 35 2.2.2.1. PD causative genes……….…………………..………………………………..….. p. 35 2.2.2.2. Susceptibility genes……….…………………..………………………………….. p. 36 2.3. Pathogenetic mechanisms of PD ……………………………………………………………….… p. 37 2.3.1. The specific vulnerability of nigral dopaminergic neurons…………………… p. 38 2.3.2. Potential mechanisms underlying neurodegeneration……………………… p. 39 2.3.2.1. Alpha-synuclein, Lewy bodies and protein aggregation………… p. 39 2.3.2.2. Impairment of protein degradation systems………………………….. p. 40 2.3.2.2.1. Ubiquitin proteasome system………………………………….... p. 41 1 2.3.2.2.2. Lysosome and chaperone mediated autophagy………… p. 42 2.3.2.3. Mitochondria and oxidative stress…………………………………….….. p. 45 2.3.2.4. Glial reaction and inflammation…………………………………….………. p. 47 3. Proteomics and Parkinson’s disease research………………………………………………………………. p. 51 3.1. “omics and PD research …………………………………………………………………………….. p. 51 3.2. Proteomics ………………………….…………………………………………………………………….. p. 53 3.2.1. Generalities…………………………………….…………………………………..…. p. 53 3.2.2. Sample preparation…………………………………….…………………………. p. 55 3.2.3. Sample separation…………………………………….…………………………… p. 56 3.2.4. Mass spectrometry and bioinformatics………………………….………. p. 58 3.2.5. Quantitative proteomics…………………………………………….….………. p. 60 4. Project presentation and aims……………………………………………………………………………………… p. 64 5. Bibliography…………………………………………………………………………………………………………………... p. 66 CHAPTER II: Proteomics in human Parkinson's disease research ……………………………………… p.81 CHAPTER III: Neuroproteomics and Parkinson’s disease: don’t forget human samples ……… p. 103 CHAPTER IV: Proteomic profiling of the substantia nigra demonstrates CNDP2 overexpression in Parkinson's disease………………………………………………………….. p. 109 CHAPTER V: Human substantia nigra proteomics: insights
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