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Sorbonne University Sorbonne University Doctoral school : « Cerveau, Cognition et Comportement » Biotechnology et Biotherapy team, ICM Brain and Spine Institute Validating Gpr88 as a new therapeutic target in models of the neuropsychiatric symptoms of Parkinson’s Disease. by Benjamin Galet PhD thesis in Neurosciences Directed by Rolando Meloni Presented and defended publicly on December 4th, 2018 In front of the following jury: Pr. Kathy DUJARDIN Professeur des Universités, Lille Rapporteur Dr. Sébastien CARNICELLA Chargé de Recherche, INSERM Rapporteur Dr. David BELIN Lecturer, University of Cambridge Examinateur Dr. Jocelyne CABOCHE Directeur de Recherche, CNRS, Paris Examinateur Dr. Jorge DIAZ Maitre de Conférences des Universités, Paris Examinateur Dr. Rolando MELONI Chargé de Recherche, CNRS Directeur de thèse Remerciements Je tiens tout d’abord à remercier Mme Kathy Dujardin et Mr Sébastien Carnicella d’avoir accepté d’être rapporteurs de ce travail de thèse. Je remercie également Mme Jocelyne Caboche, Mr David Belin, et Mr Jorge Diaz de leur participation au jury de soutenance. Je remercie sincèrement mon directeur de thèse, Rolando Meloni, de m’avoir fait confiance pour porter ce projet. J’ai beaucoup appris d’avoir travaillé avec toi, et je te suis très reconnaissant de la liberté que tu m’as accordée, ainsi que de ton aide et de ta disponibilité permanente. J’ai apprécié ta sympathie et ton sens du partage - de tes connaissances, tes anecdotes et ta culture. Je suis également très reconnaissant envers Nicole Faucon Biguet. Merci pour ton aide sans relâche, malgré les tonnes de tampons de PBS écoulés, les centaines de lames montées et les mois passés à se battre contre les « striosomes ». Je te remercie aussi de ta bienveillance et de ta générosité, pour les sandwiches post-conférence que je trouvais sur mon bureau à la sortie de l’animalerie, et de m’avoir rappelé à l’occasion que j’étais quand même un peu « toc-toc » sur les bords. Je remercie Philippe Ravassard de m’avoir accueilli dans son laboratoire, pour ses conseils précieux et sa bonne humeur. Merci aussi à toi Manuela de ton accueil et pour tout ce que tu m’as appris. Jonathan, compagnon de galère, merci pour ton aide infaillible sans laquelle je n’aurais pu faire la moitié de ce travail. Merci Anh, pour tes conseils et le temps que tu m’as accordé. Au reste de l’équipe et à tous ceux qui y sont passés – Claire, Hélène, Corinne P, Corinne F, Blandine, Clémentine, Romain, Charlotte, Nicolas, Alice, Noémie, Judith, Violetta, Mélanie, Anuya, Frédéric, Hugues et j’en oublie – merci pour votre accueil chaleureux, votre amitié et les nombreux pots de bon-vivants ! Je n’aurais pu souhaiter de débarquer dans une meilleure équipe. Merci Hélène pour tes talents de décoratrice, ton goût raffiné des belles choses et ta retenue à toute épreuve. Je remercie également Jacques Mallet pour ses conseils et nos discussions enrichissantes, ainsi que Bénédicte Bastard, Denis Guedin, Annick Prigent, Nicolas Raymont, Mélanie Huentz, Cindy Beslon, et Béatrice Moreau pour leur aide précieuse et leur sympathie. Aux camarades de paillasse, des Ajités, de l’ICM et de la fac – vous êtes trop nombreux pour tous vous citer ! Théo, Elise, Alex, Sara, Charlotte, Maha, Morwena, Lindsay, Jennifer, Jaime, Martin, Cristina, Isaac, Anna, Camille, Cynthia, Manuel, Charles, Sami, Laurène, Sean, Melissa, Julia… merci pour tous ces moments qui ont égayé ma thèse. Merci aux amis de Paris, de Bordeaux et d’ailleurs, de m’avoir rappelé qu’il y avait un monde au-delà des paillasses et des amphis. Merci à toi Audrey pour nos étés sans fin au Rosa Bonheur et nos soirées à parcourir les salles de concert de la ville. Je remercie aussi ma famille pour son soutien inconditionnel et à laquelle je dois tout. Last but not least, thank you Jordan. Close and far, through ups and downs, thank you for sticking it out with me. And for all the unbelievably delicious food along the way. Tacos forever, dude. 1 2 Table of contents Remerciements .............................................................................................................................................. 1 Table of contents ........................................................................................................................................... 3 List of abbreviations ..................................................................................................................................... 5 List of figures ................................................................................................................................................ 7 Résumé en français ....................................................................................................................................... 8 INTRODUCTION ..................................................................................................................................... 11 CHAPTER 1 - PARKINSON’S DISEASE ............................................................................................. 13 A. Symptomatology ......................................................................................................................... 14 1. Motor symptoms ....................................................................................................................... 14 2. Psychiatric symptoms .............................................................................................................. 14 3. Other non-motor symptoms.................................................................................................... 18 4. Heterogeneity and subtypes ................................................................................................... 19 B. Biological bases ............................................................................................................................ 21 1. Genetic and environmental factors ........................................................................................ 21 2. Cellular pathology .................................................................................................................... 23 3. Progression mechanisms ......................................................................................................... 25 4. Brain-wide effects ..................................................................................................................... 28 5. Associations with the psychiatric symptoms........................................................................ 35 6. A focus on the basal ganglia .................................................................................................... 37 C. Treatments .................................................................................................................................... 44 CHAPTER 2 - GPR88 ............................................................................................................................. 48 A. Studies of Gpr88 .......................................................................................................................... 49 1. Characteristics ........................................................................................................................... 49 2. Insights into Gpr88 function ................................................................................................... 52 3. Gpr88 as a therapeutic target .................................................................................................. 54 B. Relevance to Parkinson’s disease ............................................................................................. 55 CHAPTER 3 - THE RESEARCH PROJECT ......................................................................................... 56 A. Objectives ..................................................................................................................................... 56 B. Modeling Parkinson’s disease in rats ...................................................................................... 56 1. The 6-OHDA toxin ................................................................................................................... 57 2. Modeling the motor symptoms .............................................................................................. 57 3. Modeling the psychiatric symptoms ...................................................................................... 57 C. Lentiviral-mediated Gpr88 knockdown .................................................................................. 58 1. The basis: engineered RNA interference ............................................................................... 58 2. The delivery: lentiviral vectors ............................................................................................... 59 3 RESULTS .................................................................................................................................................... 61 ARTICLE 1 ............................................................................................................................................... 63 Summary ............................................................................................................................................ 63 Manuscript : Knock-down of GPR88 alters the response of medium spiny neurons to loss of DA input and L-DOPA. .............................................................................................................. 65 ARTICLE 2 ..............................................................................................................................................
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