Channel Formation by a Neurotoxic Prion Protein Fragment

Prions cause neurodegenerative disease in animals and humans. Recently it was shown that a 21-residue fragment of the prion protein (106-126) could be toxic to cultured neurons. We report here that this peptide forms ion-permeable channels in planar lipid bilayer membranes. These channels are freely permeable to common physiological ions, and their formation is significantly enhanced by “aging” and/or low pH. We suggest that channel formation is the cytotoxic mechanism of action of amyloidogenic peptides found in prion-related encephalopathies and other amyloidoses. The channels reported here are large enough and nonselective enough to mediate cell death through discharge of cellular membrane potential, changes in ionic homeostasis, and specifically, influx of calcium, perhaps triggering apoptosis. Prions cause neurodegenerative disease in animals and humans. Recently it was shown that a 21-residue fragment of the prion protein (106-126) could be toxic to cultured neurons. We report here that this peptide forms ion-permeable channels in planar lipid bilayer membranes. These channels are freely permeable to common physiological ions, and their formation is significantly enhanced by “aging” and/or low pH. We suggest that channel formation is the cytotoxic mechanism of action of amyloidogenic peptides found in prion-related encephalopathies and other amyloidoses. The channels reported here are large enough and nonselective enough to mediate cell death through discharge of cellular membrane potential, changes in ionic homeostasis, and specifically, influx of calcium, perhaps triggering apoptosis.

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