NR AWMY
AU Saghafi,S.; Lingappa,V.R.
TI Mechanisms of neurodegeneration in transmembrane and cytoplasmic PrP
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 PA-48
PT Konferenz-Poster
AB Both effects in cis and in trans have been identified to influence the biogenesis of PrP leading to changes in folding and localization. One such example is an increase in transmembrane PrP (CtmPrP) seen in genetic and infectious prion diseases, the former by a mutation in cis, the latter by an effect of PrPsc in trans. Another example is the occurrence of cytoplasmic PrP (CyPrP) leading to disease, which may be a result of leaky ribosome scanning or retrograde transport from the endoplasmic reticulum. In this study we compared the cell biological impact of CtmPrP and CyPrP expression in CHO cells. The mode of toxicity and the pathway of cell death in both cases was analyzed. Additionally we established an assay to investigate the degree of misfolding of each form by determining the proteasomal degradation profile and comparing it to the degradation profile of SecPrP, the normal secreted form of PrPc expressed predominantly by wild-type PrP. Our data leads to the conclusion that despite that the fact that both CtmPrP and CyPrP trigger cell death by a common pathway, the proteasomal degradation profile is highly dissimilar. We interpret these findings to suggest that CtmPrP is recognized by the quality control machinery as a bonafide physiological molecule; whereas CyPrP is recognized as a misfolded molecule that is subject to proteasomal degradation. This data supports our recently proposed hypothesis that CtmPrP may be a physiologic form of PrPc engaged to consummate an apoptotic program. Disease results only when CtmPrP expression is deregulated, as we have demonstrated elsewhere.
AD Institute for Neurodegenerative Diseases and Departments of Physiology, University of California, San Francisco, USA; E-mail: sam.saghafi@ucsf.edu
SP englisch
PO Italien