title: Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation.
abstract: In prion diseases, synapse dysfunction, axon retraction and loss of neuronal polarity precede neuronal death. The mechanisms driving such polarization defects, however, remain unclear. Here, we examined the contribution of RhoA-associated coiled-coil containing kinases (ROCK), key players in neuritogenesis, to prion diseases. We found that overactivation of ROCK signaling occurred in neuronal stem cells infected by pathogenic prions (PrPSc) and impaired the sprouting of neurites. In reconstructed networks of mature neurons, PrPSc-induced ROCK overactivation provoked synapse disconnection and dendrite/axon degeneration. This overactivation of ROCK also disturbed overall neurotransmitter-associated functions. Importantly, we demonstrated that beyond its impact on neuronal polarity ROCK overactivity favored the production of PrPSc through a ROCK-dependent control of 3-phosphoinositide-dependent kinase 1 (PDK1) activity. In non-infectious conditions, ROCK and PDK1 associated within a complex and ROCK phosphorylated PDK1, conferring basal activity to PDK1. In prion-infected neurons, exacerbated ROCK activity increased the pool of PDK1 molecules physically interacting with and phosphorylated by ROCK. ROCK-induced PDK1 overstimulation then canceled the neuroprotective α-cleavage of normal cellular prion protein PrPC by TACE α-secretase, which physiologically precludes PrPSc production. In prion-infected cells, inhibition of ROCK rescued neurite sprouting, preserved neuronal architecture, restored neuronal functions and reduced the amount of PrPSc. In mice challenged with prions, inhibition of ROCK also lowered brain PrPSc accumulation, reduced motor impairment and extended survival. We conclude that ROCK overactivation exerts a double detrimental effect in prion diseases by altering neuronal polarity and triggering PrPSc accumulation. Eventually ROCK emerges as therapeutic target to combat prion diseases.
authors.affiliation: INSERM, UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S 1124, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Alleaume-Butaux
authors.affiliation: INSERM, UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S 1124, Paris, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Nicot
authors.affiliation: INSERM, UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S 1124, Paris, France.
authors.forename: Mathéa
authors.initials: M
authors.lastname: Pietri
authors.affiliation: INSERM, UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S 1124, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Baudry
authors.affiliation: INSERM, UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S 1124, Paris, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dakowski
authors.affiliation: CNRS UMR 8256, Biological Adaptation and Ageing, Paris, France; Sorbonne Université, UPMC Université, Paris 06, UMR 8256, B2A, Biological Adaptation and Ageing, Institut de Biologie Paris Seine, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Tixador
authors.affiliation: INSERM, UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S 1124, Paris, France.
authors.forename: Hector
authors.initials: H
authors.lastname: Ardila-Osorio
authors.affiliation: Cytologie et Cytopathologie Neuronales, Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212, Strasbourg, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Haeberlé
authors.affiliation: Cytologie et Cytopathologie Neuronales, Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212, Strasbourg, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Bailly
authors.affiliation: CNRS UMR 8256, Biological Adaptation and Ageing, Paris, France; Sorbonne Université, UPMC Université, Paris 06, UMR 8256, B2A, Biological Adaptation and Ageing, Institut de Biologie Paris Seine, Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Peyrin
authors.affiliation: AP-HP, Service de Biochimie, INSERM UMR-S942, Hôpital Lariboisière, Paris, France; Pharma Research Department, Hoffmann La Roche Ltd, Basel, Switzerland.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.affiliation: INSERM, UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S 1124, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Kellermann
authors.affiliation: INSERM, UMR-S 1124, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S 1124, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Schneider
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D056656:Lab-On-A-Chip Devices; D051379:Mice; D008810:Mice, Inbred C57BL; D016501:Neurites / Q000378:metabolism; D055495:Neurogenesis; D018621:PrPC Proteins / Q000378:metabolism; D018620:PrPSc Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism* / Q000473:pathology*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins; D054460:rho-Associated Kinases