Relation fonctionelle entre la protéine prion cellulaire PrPc et le

ED BIO SORBONNE PARIS CITE Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-2017
Renseignements relatifs à l’Unité de Recherche :
Label et intitulé : Inserm UMR-S 1124 - Toxicologie, Pharmacologie et Signalisation Cellulaire
Nom et prénom du Directeur : BAROUKI Robert
Téléphone : 01 42 86 20 75
Télécopie : 01 42 86 38 68
Courriel: [email protected]
Renseignements relatifs à l’Equipe :
Nom de l’Equipe d’Accueil : Cellules Souches, Signalisation et Prions
Nom et prénom du responsable : SCHNEIDER Benoit / KELLERMANN Odile
Qualité du responsable : DR2 CNRS (BS) / PREX Univ. Paris Sud Orsay-ENS Ulm (OK)
Téléphone : 01 42 86 22 09 / 20 65
Télécopie : 01 42 86 20 48
Courriel : [email protected]
Renseignements relatifs au sujet de thèse :
Nom et prénom du Directeur de thèse (HDR) : SCHNEIDER Benoit
Qualité : DR2 CNRS
Téléphone : 01 42 86 22 09
Télécopie : 01 42 86 20 68
Courriel : [email protected]
Titre du sujet proposé :
Relation fonctionnelle entre la protéine prion cellulaire PrPC et le métabolisme énergétique : implications
pour les maladies à prions
Functional relationship between cellular prion protein PrPC and energetic metabolism: implications for
prion diseases
Département (cocher le département correspondant au sujet de thèse qui n’est pas obligatoirement le
vôtre) :
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Biologie Cellulaire et moléculaire, Physiologie et Physiopathologie
Immunologie
Développement Génétique Neurobiologie et Vieillissement
Infectiologie, Microbiologie
Summary (5 lines maximum) :
Cellular prion protein PrPC is known for its implication in prion diseases as corruption of PrPC function(s)
by pathogenic prions PrPSc is at the root of neurodegeneration. However, PrPC functions still remain
elusive. Based on a proteomic study with the 1C11 neuronal cell line, we evidence that PrPC silencing
alters glucose metabolism. Our aims are to delineate how PrPC takes part to energetic metabolism and if
deviation of the PrPC/energetic metabolism relationship by PrPSc contributes to neurodegeneration.
Proposition de sujet de thèse à l’appui d’une demande de contrat doctoral 2016-2017
(L’ensemble de cette fiche ne doit pas dépasser 1 page)
Nom, prénom du directeur de l'unité de recherche : BAROUKI Robert
Numéro de l'unité de recherche (et établissement de rattachement) : Inserm UMR-S1124 - Université
Paris Descartes
Nom, prénom du responsable de l'équipe d'accueil (EAD) : SCHNEIDER B. / KELLERMANN O.
Nom, prénom du directeur de thèse : SCHNEIDER Benoit
Titre du sujet de thèse proposé :
Functional relationship between cellular prion protein PrPC and energetic metabolism:
implications for prion diseases
Citer 5 mots clés : Cellular prion protein, signaling, glucose metabolism, mitochondria, prion
diseases
Candidat pressenti :
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OUI
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NON
Contenu scientifique du programme de la thèse (en anglais)
Cellular prion protein (PrPC) is a ubiquitous GPI-anchored protein that is mostly expressed in neurons.
PrPC is mainly known for its implication in prion diseases and it is clearly established that corruption of
PrPC function(s) by pathogenic prions (PrPSc) through a loss- or a gain-of-PrPC function mechanism lies
at the root of neurodegeneration. Despite intensive research on this topic, PrPC role(s) still remain(s)
elusive. Exploiting the properties of the 1C11 neuroectodermal stem cell line endowed with the capacity
to differentiate into serotonergic or noradrenergic neurons, our work permitted to assign a signaling
function to PrPC that supports PrPC roles in neuronal differentiation and homeostasis. The silencing of
PrPC in 1C11 cells (PrPnull-1C11 cells) disturbs neuronal polarity and neurotransmitter-associated
functions. These alterations are associated with modifications of actin structure and dynamics (FASEB J,
2012). Beyond the impact of PrPC down-regulation on actin cytoskeleton, a proteomic study also
revealed modifications in the expression of enzymes involved in the glycolysis pathway and oxidative
activity of mitochondria in PrPnull-1C11 cells, reflecting metabolic abnormalities caused by the absence of
PrPC. The thesis project will investigate (i) how PrPC signaling takes part to the control of glucose
metabolism in the 1C11 cell line, focusing on mitochondrial Pyruvate DeHydrogenase 1 (PDHA1), the
strong repression of which in 1C11-PrPnull cells may shift glucose oxidation by mitochondria to
fermentation, (ii) whether metabolic changes induced by PrPC depletion influence stem cell proliferation,
stem cell fate and neuronal homeostasis. (iii) Because 1C11 cells infected by PrPSc phenocopy PrPnull1C11 cells at the levels of polarity and neuronal functions (Plos Pathogens, 2015), the project will
examine whether metabolic abnormalities and underlying mechanisms revealed with PrPnull-1C11 cells
also occur within an infectious context and contribute to prion diseases. This part of the project may
unravel novel mechanisms connected to energetic metabolism by which pathogenic prions (and possibly
other amyloid proteins as Aβ peptides in Alzheimer’s disease, Nat. Med., 2013) exert their toxicity.
Indiquez les cinq meilleures publications récentes de l’équipe :
- A Alleaume-Butaux, S Nicot, M Pietri, A Baudry, C Dakowski, P Tixador, H Ardila-Osorio, AM Haeberlé, Y Bailly,
JM Peyrin, JM Launay, O Kellermann, B Schneider. Double-Edge Sword of Sustained ROCK Activation in Prion
Diseases through Neuritogenesis Defects and Prion Accumulation. 2015, PLoS Pathog. 11(8):e1005073.
- A Baudry, A Alleaume-Butaux, S Dimitrova-Nakov, M Goldberg, B Schneider, JM Launay, O Kellermann.
Essential Roles of Dopamine and Serotonin in Tooth Repair: Functional Interplay Between Odontogenic Stem Cells
and Platelets. 2015, Stem Cells. 33(8):2586-95.
- M. Pietri, C. Dakowski, S. Hannaoui, A. Alleaume-Butaux, J. Hernandez-Rapp, A. Ragagnin, S. Mouillet-Richard,
S. Haik, Y. Bailly, JM. Peyrin, JM. Launay, O. Kellermann and B. Schneider. PDK1 decreases TACE-mediated αsecretase activity and promotes disease progression in prion and Alzheimer’s diseases. 2013, Nature Medicine
19:1124-31.
- D. Loubet, C. Dakowski, M. Pietri, E. Pradines, S. Bernard, J. Callebert, H. Ardila-Osorio, S. Mouillet-Richard, JM.
Launay, O. Kellermann and B. Schneider. Neuritogenesis : the prion protein controls β1 integrin signaling activity.
2012, FASEB J. 26 :678-90.
- A. Baudry, S. Mouillet-Richard, B. Schneider, JM Launay and O. Kellermann. MiR-16 Targets the Serotonin
Transporter: A New Facet for Adaptive Responses to Antidepressants. 2010, Science. 329(5998):1537-1541.