The cellular prion protein PrP ^c is a glycosylphosphatidylinositol-anchored cell-surface protein whose biological function is unclear. We used the murine 1C11 neuronal differentiation model to search for PrP ^c -dependent signal transduction through antibody-mediated cross-linking. A caveolin-1–dependent coupling of PrP ^c to the tyrosine kinase Fyn was observed. Clathrin might also contribute to this coupling. The ability of the 1C11 cell line to trigger PrP ^c -dependent Fyn activation was restricted to its fully differentiated serotonergic or noradrenergic progenies. Moreover, the signaling activity of PrP ^c occurred mainly at neurites. Thus, PrP ^c may be a signal transduction protein.

MicroRNA-16 and Depression: Signal transmission between neurons is effected by neurotransmitters such as serotonin. Membrane-bound transporters remove excess neurotransmitters. Disruption of the delicate balance between neurotransmitter release and removal can lead to larger disruptions in neuronal circuitry. Depression and anxiety may be linked to dysfunction of some of these circuits. Uptake inhibitors can be used to treat depression, but the molecular pathways affected have been unclear. Baudry et al. (p. 1537 ) now show that microRNA-16 controls synthesis of the serotonin transporter and that the amount of microRNA-16 can be controlled by the same uptake inhibitors used to treat depression.

Putative functions of the cellular prion protein, PrP ^C , include resistance to oxidative stress, copper uptake, cell adhesion, and cell signaling. Here, we report NADPH oxidase-dependent reactive oxygen species (ROS) production and extracellular regulated kinases 1/2 (ERK1/2) phosphorylation on PrP ^C stimulation in the 1C11 neuroectodermal precursor, in its neuronal differentiated progenies, and in GT1-7 neurohypothalamic and BW5147 lymphoid cells. In neuroprogenitor, hypothalamic, and lymphoid cells, ERK1/2 activation is fully controlled by the NADPH oxidase-dependent ROS production. In 1C11-derived bioaminergic cells, ROS signaling and ERK1/2 phosphorylation are both controlled by Fyn kinase activation, introducing some specificity in PrP ^C transduction associated with this neuronal context. These data argue for an ubiquitous function of PrP ^C in cell-redox homeostasis through ROS production.

Taking advantage of three cellular systems, we established that 5-HT(2B) receptors are coupled with NO signaling pathways. In the 1C11 serotonergic cell line and Mastomys natalensis carcinoid cells, which naturally express the 5-HT(2B) receptor, as well as in transfected LMTK(-) fibroblasts, stimulation of the 5-HT(2B) receptor triggers intracellular cGMP production through dual activation of constitutive nitric-oxide synthase (cNOS) and inducible NOS (iNOS). The group I PDZ motif at the C terminus of the 5-HT(2B) receptor is required for recruitment of the cNOS and iNOS transduction pathways. Indeed, the 5-HT(2B) receptor-mediated NO coupling is abolished not only upon introduction of a competitor C-terminal 5-HT(2B) peptide in the three cell types but also in LMTK(-) fibroblasts expressing a receptor C-terminally truncated or harboring a point mutation within the PDZ domain. The occurrence of a direct functional coupling between the receptor and cNOS activity is supported by highly significant correlations between the binding constants of drugs on the receptor and their effects on cNOS activity. The 5-HT(2B)/iNOS coupling mechanisms appear more complex because neutralization of endogenous Galpha(13) by specific antibodies cancels the cellular iNOS response while not interfering with cNOS activities. These findings may shed light on physiological links between the 5-HT(2B) receptor and NO and constitute the first demonstration that PDZ interactions participate in downstream transductional pathways of a G protein-coupled receptor.

We explored simultaneously 14-3-3 protein, neuron-specific enolase (NSE), and one astroglial protein, S-100, recently proposed as Creutzfeld-Jakob disease (CJD) markers, in the cerebrospinal fluid (CSF) of 129 patients with suspected CJD. Cutoff values for NSE and S-100 were established at 25 and 2.5 ng/ml, respectively. The highest sensitivity was observed for S-100 (94.2%) followed by 14-3-3 (89.8%) and NSE (79.7%), while the highest specificity in CJD diagnosis was obtained with 14-3-3 protein (100%) as compared with NSE (91.5%) and S-100 (85.4%). No influence of sex, genotype at codon 129 of the prion protein gene, time between sampling, and death or disease duration has been found. Based on 90 cases initially referred as ‘probable’ or ‘possible’ CJD, with 14-3-3, NSE, or S-100 we could correctly discriminate between ‘CJD’ or ‘non-CJD’ categories in 94.4, 86.5, and 90% of the cases, respectively. When limited to ‘possible CJD’ cases, diagnosis based on one of the three CSF proteins was accurate in 98, 90.7 and 87.3%, respectively. In view of the fact that the CSF 14-3-3 protein test alone has the highest specificity and good sensitivity, it appears that there is no additional advantage at the moment to include NSE and/or S-100 protein in the exploration of clinically suspected CJD cases.