Cellular prion protein (PrP^C) protects neuronal cells from the effect of huntingtin aggregation

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.