CREB-dependent gene regulation by prion protein: Impact on MMP-9 and β-dystroglycan

Abstract

Corruption of the normal function of the cellular prion protein (PrP C) by the scrapie isoform (PrP Sc) emerges as a critical causal event in Transmissible Spongiform Encaphalopathies (TSE) pathogenesis. However, PrP C physiological role remains unclear. By exploiting the properties of the 1C11 neuroectodermal cell line, able to convert into 1C11 5-HT serotonergic or 1C11 NE noradrenergic neuronal cells, we assigned a signaling function to PrP C. Here, we establish that antibody-mediated PrP C ligation promotes the recruitment of the cAMP responsive element binding protein (CREB) transcription factor downstream from the MAPK ERK1/2, in 1C11 precursor cells and their 1C11 5-HT and 1C11 NE neuronal progenies. Whatever the differentiation state of 1C11 cells, the PrP C-dependent CREB activation triggers Egr-1 and c- fos transcription, two immediate early genes that relay CREB’s role in cell survival and proliferation as well as in neuronal plasticity. Furthermore, in 1C11-derived neuronal cells, we draw a link between the PrP C–CREB coupling and a transcriptional regulation of the metalloproteinase MMP-9 and its inhibitor TIMP-1, which play pivotal roles in neuronal pathophysiology. Finally, the PrP C-dependent control on MMP-9 impacts on the processing of the transmembrane protein, β-dystroglycan. Taken together, our data define molecular mechanisms that likely mirror PrP C ubiquitous contribution to cytoprotection and its involvement in neuronal plasticity.