NR AWJX
AU Mayer-Sonnenfeld,T.; Atias,H.; Friedman-Levi,Y.; Neufeld,E.F.; Gabizon,R.
TI Accumulation of gags in lisosomes delays PrPsc degradation and prolongs prion disease incubation times
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-37
PT Konferenz-Poster
AB Glycosaminoglycans (GAGs) and in particular, heparan sulfate (HS), have been shown to be associated both with prion disease pathology as well as with the metabolism of the prion proteins, and also to modulate prion infectivity. While addition of GAGs to scrapie infected cells increased PrPsc accumulation, degradation of these sulfated sugars reduced the content of PrPsc in cells. Interestingly, reagents such as Tilorone and Quinacrine, which are known to cause chemical mucopolysaccharidosis (MPS) by inducing accumulation of GAGs in lysosomes, reduce the accumulation of PrPsc in ScN2a cells. However, Quinacrine had no effect on prion disease incubation time when administered to animals after prion infection. In this work we investigated whether pathological accumulation of GAGs can induce de-novo conversion of PrPc to PrPsc, and prion infectivity. We also studied the effect of intracellular GAGs on the accumulation of PrPsc in cells. We show here that PrPsc and prion infectivity were both absent from the brains of transgenic mice ablated for GAGs degrading enzymes, thereby suffering from MPS disease and accumulate GAGs in their lisosomes. However, addition of PrPsc to cells cultured in the presence of Tilorone resulted in sequestration of the prion protein in cells for a long period of time. Interestingly, when Tilorone was administrated to mice for weeks before infection with prions, incubation time for scrapie in these animals was prolonged significantly. We propose that sequestration of PrPsc-GAGs complexes in the lysosomes, while resulting in reduced degradation of PrPsc, devoids the prion protein from its ability to convert new PrPc molecules and subsequently infect cells, thereby resulting in prolonged incubation time for the disease and reduced PrPsc accumulation in ScN2a cells.
AD T. Mayer-Sonnenfeld, H. Atias, Y. Friedman-Levi, R. Gabizon: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel; E.F. Neufeld: Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, USA
SP englisch
PO Italien