NR AXVP
AU Saghafi,S.; Lingappa,V.R.
TI Toxicity of PrPc Isoforms Dissected
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Pathology and Pathogenesis P03.91
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
It is becoming increasingly clear that pathways affecting biogenesis, maturation and degradation of the cellular prion protein (PrPc) can lead to the accumulation of alternate potentially pathologic forms. Two such forms that have been described are transmembrane CtmPrP and cytoplasmic PrP (CyPrP). It has been suggested that an inefficient N-Terminal signal sequence (SS) which results in leaky ribosome scanning can lead to the formation of CyPrP and may also contribute to the formation of CtmPrP. Alterations of topogenic elements such as the SS, the stop transfer effector (STE) domain and the transmembrane (TM) domain can modulate the formation of theses potentially toxic forms.
Here we present a study performed in cultured cells focusing on the relationship of PrPc biogenesis, maturation and degradation to the toxicity associated with CtmPrP and CyPrP expression. In general CtmPrP shows a similar maturation profile compared to the normal PrPc isoform (SecPrP) as probed by glycan maturation, SS cleavage, and degradation half life. Where as CyPrP is a preferred substrate for proteasomal degradation, remains unglycosylated with an intact SS. While upon proteasomal inhibition of wild-type PrP expressing cells CyPrP rapidly accumulates and cells show signs of cell death. Our results suggest that a smaller fraction of CtmPrP which also accumulates upon proteasomal inhibition, in this case with an uncleaved SS, is the cause for cell death. This is most dramatically revealed in a mutant that abolishes the formation of CtmPrP but does not affect CyPrP formation which shows no susceptibility to cell death by proteasomal inhibition. Our data indicate that the dependence of cells to undergo cell death is related to the capacity of PrP to form CtmPrP and does not correlate with CyPrP accumulation. In conclusion our data suggest that leaky ribosome scanning can promote the formation of both CtmPrP and CyPrP. However the toxicity observed in these conditions is likely facilitated by CtmPrP and not CyPrP in this model system. Furthermore our study provides potential insight for the unaccounted discrepancies observed in different model systems investigating the role of CyPrP.
AD S. Saghafi, V.R. Lingappa, University of California, USA
SP englisch
PO Schottland