NR AXTD
AU Mouillet-Richard,S.; Schneider,B.; Pradines,E.; Loubet,D.; Mutel,V.; Grassi,J.; Nishida,N.; Lehmann,S.; Launay,J.M.; Kellermann,O.
TI Prion Replication in Serotonergic Neuronal Cells: Impact on the Overall Serotonergic Functions
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.148
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Until now, prion-propagating cell lines have provided but little insight into the impact of PrPsc accumulation on cellular functions. We have recently introduced the 1C11 murine neuroectodermal progenitor as a novel prion-permissive cell line. A unique property of the 1C11 clone is its ability, when exposed to dbcAMP, to differentiate within 4 days into 1C115-HT neuronal cells exhibiting a complete serotonergic phenotype including serotonin (5-HT) synthesis, storage, catabolism and uptake. The acquisition of serotonin-associated functions occurs in nearly 100% cells, and follows a well-defined time-schedule. Besides, the 1C11 cell line endogenously expresses the cellular prion protein PrPc. In 1C11 precursor and 1C115-HT neuronal cells, PrPc transduces signals that take part to cell homeostasis. In a strictly neuronal context, PrPc instructs downstream cell signalling events by mobilizing a caveolin-Fyn platform at the neurites. In addition, we have described a PrPc-dependent modulation of 5-HT receptor signalling in 1C115-HT cells.
When infected with the Fukuoka strain, 1C11Fk cells retain their ability to engage into a serotonergic differentiation program. However, prion infection interferes with the implementation of a neuronal 5-HT phenotype at two levels. First, PrPsc accumulation affects the onset of a neuronal polarity. At day 4, in contrast to 1C115-HT cells that display bipolar extensions, 1C11-Fk5-HT infected cells form a heterogeneous population with over 70% cells being flat and bearing short neurites. Second, our data exemplify a drastic impact of prion infection on the overall serotonin-associated functions. We monitor a nearly 95% reduction in the ability of 1C11-Fk5-HT day 4 cells to synthesize 5-HT as compared to their uninfected counterparts. This reduction is accompanied by a deficit in 5-HT storage and an enhanced catabolism. In addition, PrPsc accumulation appears to interfere with the functionality of the membrane serotonin transporter. We assume that these alterations relate, at least partly, to a deviation of PrPc normal function by pathogenic PrPsc. Some of the prion-induced changes in 5-HT functions monitored in 1C11-Fk5-HT cells are reminiscent of observations obtained on patients or TSE-affected animals. Our findings unveil a new scenario within which alterations of neurotransmitter-associated functions in PrPsc-replicating neurones could take a proximal part in the loss of neuronal homeostasis in TSE.
AD R.S. Mouillet, CNRS, France; B. Schneider, E. Pradines, D. Loubet, O. Kellermann, CNRS, Laboratoire de Différenciation Cellulaire et Prion, France; V. Mutel, Hoffmann LaRoche, Pharma Research Department, Switzerland; J. Grassi, CEA-Saclay, iBiTech-S-SPI, France; N. Nishida, Nagasaki University, Department of Molecular Microbiology and Immunolog, Japan; S. Lehmann, CNRS, Institut de Génétique Humaine, France; J.M. Launay, Hôpital Lariboisière, Service de Biochimie, France
SP englisch
PO Schottland