NR AOXK
AU Nixon,R.R.
TI Prion associated increases in SRC-kinase
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - PG-04
PT Konferenz-Poster
AB This study investigated the relationship between the disease-associated conformer of the prion protein and levels of src-kinase. The prion diseases are characterized by spongiform degeneration, neuronal loss, and astrogliosis. Prions are composed of an abnormal conformer of a normally expressed cell surface glycoprotein. The normal protein is designated PrPc (C for "cellular") and the disease-associated conformer as PrPsc (Sc for "scrapie"). Conversion of PrPc to PrPsc is the fundamental step in prion disease pathogenesis. How this molecular event results in the characteristic neuropathologic changes is unknown. Both PrPc and PrPsc are concentrated in cholesterol and sphingolipid enriched membrane regions known as "rafts". Through unknown mechanisms, rafts sequester certain classes of proteins while excluding others thereby resulting in the lateral organization of the plasma membrane into discrete microdomains. Rafts function in signal transduction, signal processing, and endocytosis. Levels of PrPsc increase during the course of prion disease. We therefore investigated the impact of PrPsc accumulation on the level of a raft-associated signaling protein, src-kinase. These studies were performed by western blotting of N2a and ScN2a cells, as well as with two mouse models of prion disease; a transgenic model (Tg2866(MoPrP P101L)/PrPo/o) and a transmissible model (Rocky Mountain Laboratory inoculated mice). Src-kinase was increased in all three model systems. In addition, time-course studies in Tg2866(MoPrP P101L)/PrPo/o mice revealed a progressive increase in src-kinase. This increase was detected shortly after the appearance of PrPsc, but before the onset of symptoms. Similar increases in src-kinase were not seen in end-stage mice over-expressing mutant APP. These findings suggest that 1) increases in src-kinase are related to the presence of PrPsc, and 2) increases in src-kinase are not a non-specific reactive epiphenomenon.
AD R.R. Nixon, Oregon Health & Sciences University, USA
SP englisch
PO Deutschland