Abstract
The effect of normal cellular prion protein (PrP(C)) on abnormal protein aggregation was examined by transfecting huntingtin fragments (Htt) into SN56 neuronal-derived cells depleted of PrP(C) by RNA interference. PrP(C) depletion caused an increase in both the number of cells containing granules and the number of apoptotic cells. Consistent with the increase in Htt aggregation, PrP(C) depletion caused an decrease in proteasome activity and a decrease in the activities of cellular defense enzymes compared with control cells whereas reactive oxygen species (ROS) increased more than threefold. Therefore, PrP(C) may protect against Htt toxicity in neuronal cells by increasing cellular defense proteins, decreasing ROS and increasing proteasome activity thereby increasing Htt degradation. Depletion of endogenous PrP(C) in non-neuronal Caco-2 and HT-29 cells did not affect ROS levels or proteasome activity suggesting that only in neuronal cells does PrP(C) confer protection against Htt toxicity. The protective effect of PrP(C) was further evident in that overexpression of mouse PrP(C) in SN56 cells transfected with Htt caused a decrease in both the number of cells with Htt granules and the number of apoptotic cells, whereas there was no effect of PrP(C) expression in non-neuronal NIH3T3 or CHO cells. Finally, in chronically scrapie (PrP(Sc))-infected cells, ROS increased more than twofold while proteasome activity was decreased compared to control cells. Although this could be a direct effect of PrP(Sc), it is also possible that, since PrP(C) specifically prevents pathological protein aggregation in neuronal cells, partial loss of PrP(C) itself increases PrP(Sc) aggregation.
Highlights
The normal cellular prion protein (PrPC) is a glycosylphosphatidylinositol-anchored glycoprotein that is predominantly expressed in the brain (Prusiner, 1998; Weissmann and Flechsig, 2003)
There have been numerous models proposed for the neuronal cell loss and spongiform changes in the brain that occur in scrapie, but it is still not clear whether this pathology is due to a loss of functional PrPC or only to a gain of function by PrPSc
Clinical symptoms can occur without any obvious scrapie deposits (Collinge et al, 1990; Medori et al, 1992), which has led to the suggestion that the loss of normal PrPC function, not formation of PrPSc deposits, causes prion disease (Aguzzi and Weissmann, 1997)
Summary
The normal cellular prion protein (PrPC) is a glycosylphosphatidylinositol-anchored glycoprotein that is predominantly expressed in the brain (Prusiner, 1998; Weissmann and Flechsig, 2003). The protease-resistant misfolded scrapie isoform of prion protein (PrPSc) is the causative agent of transmissible spongiform encephalopathies, which are neurodegenerative disorders that include scrapie in sheep and goats, bovine spongiform encephalopathies, chronic wasting disease in deer and elk and Creutzfeldt-Jakob disease in humans (Prusiner, 1998) In all of these disorders, exposure of nerve cells to PrPSc converts PrPC to aggregated deposits of PrPSc. There have been numerous models proposed for the neuronal cell loss and spongiform changes in the brain that occur in scrapie, but it is still not clear whether this pathology is due to a loss of functional PrPC or only to a gain of function by PrPSc. Clinical symptoms can occur without any obvious scrapie deposits (Collinge et al., 1990; Medori et al, 1992), which has led to the suggestion that the loss of normal PrPC function, not formation of PrPSc deposits, causes prion disease (Aguzzi and Weissmann, 1997). Altered neuronal excitability can predispose individuals to neuronal damage and death (Leist and Nicotera, 1998) so it is possible that loss of
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