Neurotoxicity of the putative transmembrane domain of the prion protein

It has been shown recently that the generation of an abnormal transmembrane form of the prion protein ((PrP)-Pr-Ctm) is involved in the neurodegenerat ion process during inherited and infectious prion diseases but a causative relationship has never been established. We wanted to know if and how the p roposed transmembrane domain of PrP could induce neuronal dysfunction. Thus , we investigated the neurotoxic properties of two peptides whose sequences are encompassed within this domain. We show that PrP peptides 118-135 and 105-132 as well as an amidated more soluble peptide 105-132 induce the deat h of pure cortical neurons originating from normal and PrP knockout mice. T his can be correlated with the high propensity of these peptides to insert stably into and to destabilize cell membranes. Through this study, we have identified a novel mechanism of neurotoxicity for PrP, which directly invol ves membrane perturbation; this mechanism is independent of fibril formatio n and probably corresponds to the effect of the transmembrane insertion of (PrP)-Pr-Ctm. (C) 2000 Academic Press.