Cellular prion protein coupling to TACE-dependent TNF-α shedding controls neurotransmitter catabolism in neuronal cells

Despite considerable efforts to unravel the role of cellular prion protein (PrPC) in neuronal functions, the mechanisms by which PrPC 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 PrPC to bioaminergic cell functions. We established that in 1C11-derived neuronal cells antibody-mediated PrPC ligation triggered tumor necrosis factor (TNF)-alpha release, through recruitement of the metalloproteinase TNF-alpha converting enzyme (TACE). TNF-alpha shed in response to PrPC 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 PrPC-dependent modulator of neuronal metabolism. Of note, we previously reported on a control of neurotransmitter catabolism by 5-HT2B 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 PrPC and these two bioaminergic receptors add their effects on neurotransmitter degradation. Overall, these observations unveil a novel contribution of PrPC to the control of neuronal functions and may have implications regarding dysfunction of the bioaminergic systems in prion diseases.