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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Channels formed with a mutant prion protein PrP(82-146) homologous to a 7-kDa fragment in diseased brain of GSS patients

¹Membrane Transport Group, Department of Chemistry, The Faculties, The Australian National University, Canberra, Australian Capital Territory 0200, Australia; ²Istituto Neurologico Carla Besta, 20133 Milan; and ³Istituto di Richerche Farmacologiche Mario Negri, 20157 Milan, Italy

Submitted 26 February 2003 ; accepted in final form 23 May 2003

A major prion protein (PrP) mutant that forms amyloid fibrils in the diseased brain of patients with Gerstmann-Sträussler-Scheinker syndrome (GSS) is a fragment of 7 kDa spanning from residues 81-82 to 144-153 of PrP. Analysis of ionic membrane currents, recorded with a libid bilayer technique, revealed that the wild-type fragment PrP(82-146) WT and the partially scrambled PrP(82-146) (127-146) SC are capable of forming heterogenous ion channels that are similar to those channels formed with PrP(106-126). In contrast, PrP(82-146) peptides in which the region from residue 106 to 126 had been scrambled (SC) showed a reduction in interaction with lipid membranes and did not form channels. The PrP(82-146) WT- and PrP(82-146) (127-146) SC-formed cation channels with fast kinetics are Cu²⁺ sensitive and rifampicin (RIF) insensitive, whereas the time-dependent inactivating channels formed by these same peptides are both Cu²⁺ and RIF insensitive. The presence of RIF in the solution before the addition of PrP(82-146) WT or PrP(82-146) (127-146) SC affected their incorporation into the lipid bilayers. PrP(82-146) WT and PrP(82-146) (127-146) SC fast cation channels formed in the presence of RIF appeared in an electrically semisilent state or an inactivated state. Increasing [Cd²⁺]_cis enhanced the incorporation of PrP(82-146) WT and PrP(82-146) (127-146) SC channels formed in the presence of RIF. We conclude that the major PrP mutant fragment in the diseased brain of GSS patients is prone to form channels in neuronal membranes, causing their dysfunction. We propose that Cd²⁺ may accentuate the neurotoxicity of this channel-forming PrP fragment by enhancing its incorporation into the membrane.

prion diseases; prion channels; amyloids; neurodegenerative diseases; membrane-linked pathologies; vacuolation; cytotoxic proteins

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