PrP^Scaccumulation in neuronal plasma membranes links Notch-1 activation to dendritic degeneration in prion diseases

Prion diseases are disorders of protein conformation in which PrP^C, the normal cellular conformer, is converted to an abnormal, protease-resistant conformer rPrP^Sc. Approximately 80% of rPrP^Sc accumulates in neuronal plasma membranes where it changes their physical properties and profoundly affects membrane functions. In this review we explain how rPrP^Sc is transported along axons to presynaptic boutons and how we envision the conversion of PrP^C to rPrP^Sc in the postsynaptic membrane. This information is a prerequisite to the second half of this review in which we present evidence that rPrP^Sc accumulation in synaptic regions links Notch-1 signaling with the dendritic degeneration. The hypothesis that the Notch-1 intracellular domain, NICD, is involved in prion disease was tested by treating prion-infected mice with the γ-secretase inhibitor (GSI) LY411575, with quinacrine (Qa), and with the combination of GSI + Qa. Surprisingly, treatment with GSI alone markedly decreased NICD but did not prevent dendritic degeneration. Qa alone produced near normal dendritic trees. The combined GSI + Qa treatment resulted in a richer dendritic tree than in controls. We speculate that treatment with GSI alone inhibited both stimulators and inhibitors of dendritic growth. With the combined GSI + Qa treatment, Qa modulated the effect of GSI perhaps by destabilizing membrane rafts. GSI + Qa decreased PrP^Sc in the neocortex and the hippocampus by 95%, but only by 50% in the thalamus where disease was begun by intrathalamic inoculation of prions. The results of this study indicate that GSI + Qa work synergistically to prevent dendrite degeneration and to block formation of PrP^Sc.