Ion channels induced by the prion protein Mediators of neurotoxicity

Prion diseases comprise a group of rapidly progressive and invariably fatal neurodegenerative disorders for which there are no effective treatments. While conversion of the cellular prion protein (PrPC) to a beta-sheet rich isoform (PrPSc) is known to be a critical event in propagation of infectious prions, the identity of the neurotoxic form of PrP and its mechanism of action remain unclear. Insights into this mechanism have been provided by studying PrP molecules harboring deletions and point mutations in the conserved central region, encompassing residues 105-125. When expressed in transgenic mice, PrP deleted for these residues (Delta 105-125) causes a spontaneous neurodegenerative illness that is reversed by co-expression of wild-type PrP. In cultured cells, Delta 105-125 PrP confers hypersensitivity to certain cationic antibiotics and induces spontaneous ion channel activity that can be recorded by electrophysiological techniques. We have utilized these drug-hypersensitization and current-inducing activities to identify which PrP domains and subcellular locations are required for toxicity. We present an ion channel model for the toxicity of Delta 105-125 PrP and related mutants and speculate how a similar mechanism could mediate PrPSc-associated toxicity. Therapeutic regimens designed to inhibit prion-induced toxicity, as well as formation of PrPSc, may prove to be the most clinically beneficial.