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Modulation of the JAK2/STAT3 Pathway in Vivo: Understanding Reactive Astrocyte Functional Features and Contribution to Neurodegenerative Diseases

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Modulation of the JAK2/STAT3 pathway in vivo : understanding reactive astrocyte functional features and contribution to neurodegenerative diseases Lucile Ben Haim To cite this version: Lucile Ben Haim. Modulation of the JAK2/STAT3 pathway in vivo : understanding reactive astrocyte functional features and contribution to neurodegenerative diseases. Neurons and Cognition [q-bio.NC]. Université Pierre et Marie Curie - Paris VI, 2014. English. NNT : 2014PA066534. tel-01165032 HAL Id: tel-01165032 https://tel.archives-ouvertes.fr/tel-01165032 Submitted on 18 Jun 2015 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Université Pierre et Marie Curie Ecole Doctorale Cerveau, Cognition, Comportement Laboratoire des maladies neurodégénératives, CEA-CNRS URA2210 Thèse de doctorat de Neurosciences Lucile BEN HAIM Modulation of the JAK2/STAT3 pathway in vivo: understanding reactive astrocyte functional features and contribution to neurodegenerative diseases. Dirigée par Dr. Carole Escartin Soutenue publiquement le 11 décembre 2014 Composition du jury Président Pr. Jean Mariani CNRS UMR 7102 UPMC Rapporteurs Dr. Jean-Charles Liévens CNRS UMR 7286 CRN2M Dr. Frank Pfrieger CNRS UPR 3212 INCI Examinateurs Dr. Christian Lobsiger INSERM U-1127 UPMC Dr. Stéphane Oliet INSERM Neurocentre Magendie Directrice de thèse Dr. Carole Escartin CEA-CNRS URA2210 1 « Before you know, you must imagine » Nobel laureate Richard Axel 2 Abstract Astrocytes become reactive in response to pathological conditions in the CNS including neurodegenerative diseases (ND) such as Alzheimer’s (AD) and Huntington’s (HD) diseases. Reactive astrocytes (RA) are identified by morphological changes but their functional features and influence on neuronal survival are poorly understood. They have mainly been studied in acute injuries, but less is known for chronic diseases like ND. In this context, we aimed at 1) identifying the signaling cascades involved in astrocyte reactivity in ND conditions, 2) evaluating RA contribution to chronic neuronal dysfunction in ND models and 3) deciphering RA functional features. The JAK2/STAT3 pathway is a known trigger of astrocyte reactivity in many CNS acute injury models. Here, we show that this pathway is a universal inducer of astrocyte reactivity in several ND mouse models of both AD and HD. We developed new viral vectors that target the JAK2/STAT3 cascade in vivo, in astrocytes of the adult rodent brain, to selectively modulate astrocyte reactivity. Using these original tools, we were able to investigate the contribution of RA to disease progression and neuronal dysfunction in two different models of HD: the lentiviral-based model of HD and the N171-82Q HD mice. Our results show that RA do not primarily influence disease phenotype in these models. Finally, we manipulated the JAK2/STAT3 pathway to activate astrocytes in WT mice in order to characterize the functional features of RA in vivo. We show that astrocyte activation through the JAK2/STAT3 pathway triggers transcriptional changes of numerous genes involved in important cellular functions such as metabolism, protein degradation pathways and immune response. Furthermore, we show that astrocyte reactivity alters synaptic plasticity in the mouse hippocampus. Our results identify the JAK2/STAT3 pathway as a central cascade for astrocyte reactivity. The viral vectors developed in this project represent powerful tools to 1) manipulate this pathway and decipher RA contribution to chronic neuronal dysfunction in various ND models and 2) characterize RA functional features in vivo. Better understanding RA functions may eventually lead to the identification of new therapeutic targets for ND. Key words: Reactive astrocytes, JAK2/STAT3 pathway, Neuroinflammation, Huntington’s disease, Alzheimer’s disease, Viral vectors, Transcription regulation. Résumé Les astrocytes deviennent réactifs en réponse à toute situation pathologique dans le SNC, en particulier dans les maladies neurodégératives (MND) comme la maladie d’Alzheimer (MA) et de Huntington (MH). Les astrocytes réactifs (AR) sont identifiés par des changements morphologiques bien caractérisés mais les conséquences fonctionnelles de leur réactivité sont peu connues, notamment dans les MND. La contribution des AR dans les situations pathologiques a principalement été étudiée dans des modèles de lésions aigües mais leur rôle dans les MND est peu connu. Dans cette étude, nous avons évalué 1) les voies de signalisation impliquées dans la réactivité astrocytaire, 2) la contribution des AR à la dysfonction neuronale dans des modèles de MND et 3) les caractéristiques fonctionnelles des AR. La voie JAK2/STAT3 est une voie de signalisation impliquée dans la réactivité astrocytaire, dans des conditions pathologiques aigües. Dans cette étude, nous avons montré que cette voie universelle induit également la réactivité astrocytaire des modèles murins de MA et MH. Nous avons développé de nouveaux vecteurs viraux permettant de cibler la voie JAK2/STAT3, in vivo, sélectivement dans les astrocytes, dans le cerveau de rongeur adulte. A l’aide de ces outils, nous avons étudié la contribution des AR à la dysfonction neuronale observée dans deux modèles murins de la MH. Nos résultats suggèrent que les AR ne jouent pas un rôle central dans la dysfonction neuronale et la progression de la maladie dans ces deux modèles. Enfin, nous avons induit la réactivité dans les astrocytes de souris sauvages, en ciblant la voie JAK2/STAT3. L’activation de la voie JAK2/STAT3 dans les astrocytes du striatum module très fortement l’expression de gènes impliqués dans des fonctions cellulaires importantes comme le métabolisme oxydatif, les voies de dégradation des protéines ou la réponse immunitaire. De plus, nous avons observé que l’induction de la réactivité astrocytaire dans l’hippocampe de souris sauvage conduit à une diminution de la plasticité synaptique. En conclusion, nous avons montré que la voie JAK2/STAT3 est une voie centrale et conservée dans les AR. Les vecteurs viraux développés au cours de ce projet représentent des outils innovants pour évaluer 1) la contribution des AR à la dysfonction neuronale dans de nombreux modèles de MND et 2) caractériser les propriétés fonctionnelles des AR in vivo. L’étude des AR pourra permettre d’identifier de nouvelles cibles moléculaires pour manipuler ces cellules pléiotropes à des fins thérapeutiques. Mots-clés : Astrocytes réactifs, Voie de signalisation JAK2/STAT3, Neuroinflammation, Maladie de Huntington, Maladie d’Alzheimer, Vecteurs viraux, Régulation transcriptionnelle 3 Remerciements Je tiens à remercier les membres de mon jury pour avoir accepté d’examiner mon travail et de participer à ma soutenance de thèse. En particulier mes rapporteurs Jean-Charles Liévens et Frank Pfrieger pour l’évaluation de mon manuscrit. Je voudrais remercier toutes les personnes qui m’ont aidé, de toutes les manières que ce soit, au cours de ma thèse. Je remercie Philippe Hantraye pour avoir accepté que je réalise mon stage de Master 2 et ma thèse à MIRCen. Je voudrais remercier ma directrice de thèse, Carole, qui aura éprouvé, en plus de ces deux grossesses, une sorte de troisième accouchement en encadrant officiellement sa première thèse. Merci pour tes encouragements constants, à l’épreuve de mon pessimiste et de mon instatisfaction. Merci pour ton encadrement, pour la confiance que tu m’as accordé, dès le Master 2 sur ce projet. Merci de m’avoir permis de présenter mon travail et de le défendre à de nombreux congrès. Merci de ton aide, de ton soutien et de tes conseils pour la thèse et aussi pour la suite. Je tiens à remercier Gilles pour avoir été mon maître de stage de Master 2 par intérim, pour ton expérience, tes conseils, tes encouragements et pour l’organisation des team-meetings qui m’ont fait beaucoup progressé sur la communication de mes résultats (pour la partie valorisation, ça vient petit à petit). Merci à Emmanuel pour m’avoir accueillie dans le laboratoire et encadré au cours de mon stage de Master 1. Merci pour ta gentillesse, pour le temps que tu as toujours su m’accorder pour parler de mon projet de thèse, de science en général ou de la carrière de chercheur. Merci aux différentes personnes qui ont partagé mon bureau pour avoir éprouvé ma taciturnité au cours de ces trois ans et demi. Laetitia, merci pour ton optimisme, ton calme et ton humour (pas toujours bien placé), pour nos discussions existentielles sur la thèse et sur la suite. Merci à Noémie pour ta bonne humeur et ton humour, malgré que tu aies partagé notre bureau au cours des mois les plus stressants de ces 3 ans. Bon courage pour la suite. Merci à María pour ton soutien, tes encouragements et ta sagesse, de laquelle je vais m’efforcer de m’inspirer en recherche et dans la vie en général. Merci à Fabien pour ton aide, qui a été très précieuse pour mon projet de thèse mais surtout merci pour ton humour qui nous manque à tous. Merci à Juliette et Emilie pour leur soutien, leur humour et tous les moments qu’on a partagé. Juliette, nos échanges 9gag resteront associés à ma thèse pour toujours. Emilie, tu es un exemple de courage et de persévérance (et aussi de résistance à la bière). Merci à Karine pour m’avoir formée et pour ton aide pour les expériences de comportement. Je garde un souvenir tout particulier de l’atelier peinture pour le test de la marche. Merci à Marie-Claude pour m’avoir formée à la qPCR, pour ton aide et tes nombreux conseils. Merci à Noëlle, Charlène, Nicole et Alexis pour le design et la production des quelqu…nombreux virus dont je me suis servie au cours de ma thèse.
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