NR AOCW
AU Prusiner,S.B.
TI Biology of Prion Diseases
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Oral sessions ORAL-01
PT Konferenz-Vortrag
AB
Recent studies argue that PrPc functions as a signal transduction molecule that binds to N-CAM (1). Overnight exposure of cultured fetal hippocampal neurons to recPrP, folded into an alpha-helical conformation similar to PrPc, resulted in a two-fold increase in neurons with a differentiated axon, a 14-fold increase in neurons with differentiated dendrites, a five-fold increase in axon length, and the formation of extensive neuronal circuitry. Neither the N-terminal nor C-terminal domains of recPrP nor the PrP paralogue doppel enhanced neuronal polarization. Inhibitors of PKC and of Src kinases, including p59Fyn, blocked the effect of recPrP on axon elongation, suggesting that recPrP stimulates signaling cascades involving these kinases. That the mammalian prion contains only PrPsc, and thus that prions are infectious proteins, has been demonstrated using recPrP. Two distinct prion strains have been produced using recPrP: (1) MoSP1 exhibits protease-resistant PrPsc and extreme resistance to GdnHCl denaturation and (2) MoSP2 shows protease-sensitive PrPsc. MoSP1 could be propagated in mice expressing full-length or N-terminally truncated PrP while MoSP2 could replicate only in mice expressing truncated PrP. Protease-sensitive PrPsc can be detected by the conformation-dependent immunoassay. Towards developing a more sensitive and specific presymptomatic diagnostic test for prion disease, we synthesized a series of Keggin-type polyoxometalate (POM) complexes, which demonstrated superior ability to precipitate PrPsc selectively. Our results suggest that prion aggregation may involve multivalent electrostatic interactions between the POM anions and positively charged cleft sites of PrPsc.
Reference
1. Santuccione, A., Sytnyk, V., Leshchyns'ka, I. & Schachner, M. (2005) J. Cell Biol. 169, 341-354.
AD Stanley B. Prusiner, Institute for Neurodegenerative Diseases and Departments of Neurology and of Biochemistry and Biophysics, University of California, San Francisco, CA, USA
SP englisch
PO Deutschland