Cellular prion protein coupling to TACE-dependent TNF-alpha shedding controls neurotransmitter catabolism in neuronal cells.
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.
Pradines
Elodie
E
Laboratoire Cellules Souches, Signalisation et Prions, Université Paris Descartes, Paris, France.
Loubet
Damien
D
Mouillet-Richard
Sophie
S
Manivet
Philippe
P
Launay
Jean-Marie
JM
Kellermann
Odile
O
Schneider
Benoît
B
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
D018377:Neurotransmitter Agents; D011328:Prions; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse