title: Cellular prion protein coupling to TACE-dependent TNF-alpha shedding controls neurotransmitter catabolism in neuronal cells.
abstract: Despite considerable efforts to unravel the role of cellular prion protein (PrP(C)) in neuronal functions, the mechanisms by which PrP(C) takes part in the homeostasis of a defined neuronal phenotype remain poorly characterized. By taking advantage of a neuroectodermal cell line (1C11) endowed with the capacity to differentiate into serotonergic (1C11(5-HT)) or noradrenergic (1C11(NE)) neurons, we assessed the contribution of PrP(C) to bioaminergic cell functions. We established that in 1C11-derived neuronal cells antibody-mediated PrP(C) ligation triggered tumor necrosis factor (TNF)-alpha release, through recruitment of the metalloproteinase TNF-alpha converting enzyme (TACE). TNF-alpha shed in response to PrP(C) acts as a second message signal, eliciting serotonin (5-HT) or norepinephrine (NE) degradation in 1C11(5-HT) or 1C11(NE) cells, respectively. Our data thus introduced TNF-alpha as a PrP(C)-dependent modulator of neuronal metabolism. Of note, we previously reported on a control of neurotransmitter catabolism by 5-HT(2B) or alpha(1D) autoreceptors in 1C11 bioaminergic neurons, via the same TACE/TNF-alpha pathway (Ann. N Y Acad. Sci. 1091, 123). Here, we show that combined stimulation of PrP(C) and these two bioaminergic receptors add their effects on neurotransmitter degradation. Overall, these observations unveil a novel contribution of PrP(C) to the control of neuronal functions and may have implications regarding dysfunction of the bioaminergic systems in prion diseases.
authors.affiliation: Laboratoire Cellules Souches, Signalisation et Prions, Université Paris Descartes, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Pradines
authors.forename: Damien
authors.initials: D
authors.lastname: Loubet
authors.forename: Sophie
authors.initials: S
authors.lastname: Mouillet-Richard
authors.forename: Philippe
authors.initials: P
authors.lastname: Manivet
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.forename: Odile
authors.initials: O
authors.lastname: Kellermann
authors.forename: Benoît
authors.initials: B
authors.lastname: Schneider
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism / Q000502:physiology*; D000072198:ADAM17 Protein; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D008660:Metabolism / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011328:Prions / Q000378:metabolism* / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000502:physiology
chemical_list: D018377:Neurotransmitter Agents; D011328:Prions; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse