PrP overdrive Does inhibition of α-cleavage contribute to PrPC toxicity and prion disease?

Knockout of the cellular prion protein (PrPC) in mice is tolerated, as is complete elimination of the protein's N-terminal domain. However, deletion of select short segments between the N- and C-terminal domains is lethal. How can one reconcile this apparent paradox? Research over the last few years demonstrates that PrPC undergoes alpha-cleavage in the vicinity of residue 109 (mouse sequence) to release the bioactive N1 and C1 fragments. In biophysical studies, we recently characterized the action of relevant members of the ADAM (A Disintegrin And Metalloproteinase) enzyme family (ADAM8, 10, and 17) and found that they all produce alpha-cleavage, but at three distinct cleavage sites, with proteolytic efficiency modulated by the physiologic metals copper and zinc. Remarkably, the shortest lethal deletion segment in PrPC fully encompasses the three alpha-cleavage sites. Analysis of all reported PrPC deletion mutants suggests that elimination of alpha-cleavage, coupled with retention of the protein's N-terminal residues, segments 23-31 and longer, confers the lethal phenotype. Interestingly, these N-terminal residues are implicated in the activation of several membrane proteins, including synaptic glutamate receptors. We propose that alpha-cleavage is a general mechanism essential for downregulating PrPC's intrinsic activity, and that blockage of proteolysis leads to constitutively active PrPC and consequent dyshomeostasis.