UC Santa Cruz

The misfolding of the cellular prion protein (PrPC) into the aggregate prone conformer (PrPSc) is at the heart of a class of neurodegenerative diseases called transmissible spongiform encephalopathies (TSEs). These diseases affect humans, bovine, sheep, and other mammals. PrPC is a well conserved mammalian protein and is highly expressed in the brain. PrPC is composed of two main domains consisting of the unstructured N-terminus and the structured C-terminus. The two main domains are connected by a short linker called the central region (CR). Previous studies have shown internal amino-proximal deletions spanning the CR generate a profound neurotoxicity in mice. The toxicity generated by these deletions have been shown to parallel bona fide prion diseases, and thus making them a good model system for studying prion diseases. The neurotoxicity elicited by CR deletion mutants is thought to originate from a misregulation of the extreme N-terminus of PrPC. However, these deletion mutants make two major changes that could potentially lead to the misregulation of the N-terminus. These include: 1) weakening of a protective metal-driven cis-interaction, and 2) deletion of the locus important in a regulatory cleavage event. This study used designed mutations to allow for one of these changes at a time while not altering the other. We find that neither blocking the metal-driven cis-interaction nor cleavage generates toxicity. Conversely, we show that the WT PrPC CR sequence is necessary for regulating the toxicity. Moreover, we find that the WT PrPC CR sequence is necessary for PrPC homodimerization on the cell surface, which could be a protective mechanism from the deleterious effects of a misregulated extreme N-terminus. Additionally, we found that pathological mutations in the CR causing a certain set of prion diseases in humans do not affect the metal-driven cis-interaction. Furthermore, these result suggests a difference in the origin of neurotoxicity between CR pathological mutations and C-terminal pathological mutations.