NR AOBG
AU Bahadi,R.; Farrelly,P.V.; Kenna,B.L.; Kourie,J.I.; Tagliavini,F.; Forloni,G.; Salmona,M.
TI Ion channels formed with a synthetic mutant prion protein (PrP[[!LB]]82-146[[!RB]]) homologous to a 7 kDa fragment found in the diseased brain of Gerstmann-Sträussler-Scheinker syndrome
QU American Journal of Physiology. Cell Physiology 2003 Jun 18
PT journal article
AB A major prion protein (PrP) mutant fragment which forms amyloid fibrils in the diseased brain of Gerstmann-Sträussler-Scheinker syndrome (GSS) is a fragment of 7 kDa spanning from residues 81-82 to 144-153 of PrP. In this study we are using the lipid bilayer technique to record ionic currents and deduce the ability of homologues and fully or partially scrambled (SC) peptides to this 7 kDa PrP fragment to interact with and permeabilise lipid membranes. Analysis of ionic membrane currents 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 residue 126 had been scrambled, e.g. PrP[82-146] SC and PrP[82-146] (106-126) SC showed a reduction in interaction with lipid membranes and did not form ion channels. The PrP[82-146] WT and PrP[82-146] (127-146) SC-formed cation channels with fast kinetics are Cu(2+)-sensitive and rifampicin- (RIF) insensitive whereas the time-dependent inactivating channels formed by these same peptides are both Cu(2+)-insenstitive and RIF-insensitive. The presence of RIF in the solution prior to the addition of PrP[82-146] WT or PrP[82-146] (127-146) SC affected their incorporation into the lipid bilayers. In addition, the PrP[82-146] WT and PrP[82-146] (127-146) SC fast cation channels formed in the presence of RIF, appeared in an electrically semi-silent state or in an inactivated state. Increasing [Cd(2+)]cis enhanced the incorporation 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 is prone to form ion channels in neuronal membranes causing their dysfunction and that leads to fatal familial insomnia. It is proposed that Cd(2+) may accentuate neurotoxicity of this channel-forming PrP fragment by enhancing its incorporation into the membrane. It is proposed that the pharmacological approach that involves preventing assembly and incorporation of channel-forming amyloid intermediates into membranes could be a common therapeutic strategy for amyloid-linked pathologies.
AD Department of Chemistry, The Australian National University, Canberra, ACT, Australia.
SP englisch