NR ABSM
AU Brown,D.R.
TI Altered toxicity of the prion protein peptide PrP106-126 carrying the Ala(117) -> Val mutation
QU Biochemical Journal 2000 Mar 15; 346 Pt 3: 785-91
PT journal article
AB The inherited prion diseases such as Gerstmann-Sträussler-Scheinker syndrome (GSS) are linked to point mutations in the gene coding for the cellular isoform of the prion protein (PrPc). One particular point mutation A117V (Ala(117) -> Val) is linked to a variable pathology that usually includes deposition of neurofibrillary tangles. A prion protein peptide carrying this point mutation [PrP106-126(117V)] was generated and compared with a peptide based on the normal human sequence [PrP106-126(117A)]. The inclusion of this point mutation increased the toxicity of PrP106-126 which could be linked to an increased beta-sheet content. An assay of microtubule formation in the presence of tau indicated that PrP106-126 decreased the rate of microtubule formation that could be related to the displacement of tau. PrP106-126 carrying the 117 mutation was more efficient at inhibiting microtubule formation. These results suggest a possible mechanism of toxicity for protein carrying this mutation via destabilization of the cytoskeleton and deposition of tau in filaments, as observed in GSS.
MH Alanine/*chemistry; Amino Acid Sequence; Amino Acid Substitution; Animal; Biopolymers; Cells, Cultured; Circular Dichroism; Human; Mice; Mice, Knockout; Microscopy, Electron; Molecular Sequence Data; Mutation; Peptide Fragments/chemistry/genetics/*toxicity; Prions/chemistry/genetics/*toxicity; Protein Structure, Secondary; Support, Non-U.S. Gov't; Tubulin/antagonists & inhibitors/chemistry; Valine/*chemistry
AD Department of Biochemistry, Cambridge University, Tennis Court Road, Cambridge CB2 1QW, U.K. drb33@cam.ac.uk
SP englisch
PO England