NR AWKT
AU Mouillet-Richard,S.; Nishida,N.; Laude,H.; Schneider,B.; Kettler,R.; Feraudet,C.; Grassi,J.; Launay,J.M.; Lehmann,S.; Kellermann,O.
TI Prion infection interferes with the serotonergic differentiation of the murine 1c11-neuronal progenitor
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions CE-33
PT Konferenz-Poster
AB Prion-propagating cell lines represent valuable tools to investigate into the biogenesis, conversion and trafficking Sc of the scrapie prion protein PrP, and have been exploited for diagnostic and therapeutic assays. In contrast, Sc relatively little information has been gathered on the impact of PrP accumulation on cellular functions. We took advantage of the 1C11 murine neuroectodermal progenitor, able to acquire upon induction the overall functions 5-HT cells), to assess the impact of prion replication on the implementation of a of serotonergic neurones (1C11 defined neuronal differentiation program. The EC-derived 1C11 clone behaves as a neuronal stem cell. Exposure of 1C11 cells to dbcAMP triggers the synchronous and homogenous onset of pan-neuronal and neurotransmitter-specific markers, reaching a complete serotonergic phenotype, including synthesis, storage, catabolism and uptake, within four days. The 1C11 cell line endogenously expresses the cellular prion protein PrPc and has been instrumental in defining PrPc as a signalling molecule. 1C11 undifferentiated cells were incubated with brain homogenates from prion-infected mice and tested for their capacity to accumulate proteinase-K resistant PrP. Significant PrPres accumulation could be detected in 1C11 cells exposed to the Chandler, 22L and, most notably, Fukuoka, strains. Several clones (1C11-Fk) with various levels of PrPres production were derived from the Fukuoka-infected cell population. Inoculation to tga20 mice allowed us to establish that prion-replicating 1C11-Fk clones carry infectivity. 1C11-Fk infected cells were then tested for their ability to differentiate into serotonergic neuronal-like cells upon induction. From a morphological point of view, prion infection interferes with the proper onset of neuronal polarity. While 1C115-HT day 4 cells display bipolar extensions, 1C11-Fk5-HT day 4 cells form a heterogeneous population with over 70% cells being flat and bearing C short neurites. In view of the proposed role of PrP in neurite outgrowth, this aberrant morphology could be accounted for by an alteration of PrPc normal function due to prion replication. A drastic impact of prion infection 5-HT day 4 cells exhibit could further be measured at the level of serotonin-associated functions. Indeed, 1C11-Fk significantly lowered rates of serotonin synthesis and an altered serotonin metabolism. The 1C11 cell system provides a novel model to decipher the impact of PrPsc accumulation on PrPc normal function at a molecular level, notably with respect to PrPc signalling activity. It may help design strategies aimed C at abrogating prion replication while preserving PrP biological activity.
AD S. Mouillet-Richard, B. Schneider, O. Kellermann: Différenciation cellulaire et prions, CNRS FRE2937 94801 Villejuif, France & Institut Pasteur, Département de biologie cellulaire et Infections, 75724 Paris Cedex 15, France; N. Nishida: IGH, CNRS UPR 1142, 34396 Montpellier Cedex 5, France, and Department of Molecular Microbiology & Immunology, Nagasaki University Graduate School of Medical Science, Nagasaki 852-8523, Japan; H. Laude: INRA - VIM, 78350 Jouy en Josas, France; R. Kettler: Hoffmann-LaRoche, Basel, Switzerland; C. Féraudet, J. Grassi: CEA-Saclay, DSV-SPI, 91191 Gif sur Yvette Cedex, France; J.M. Launay: Hôpital Lariboisière 75009 Paris, France; S. Lehmann: IGH, CNRS UPR 1142, 34396 Montpellier Cedex 5, France. E-mail: mouillet@vjf.cnrs.fr
SP englisch
PO Italien