title: Altered toxicity of the prion protein peptide PrP106-126 carrying the Ala(117)-->Val mutation.
abstract: 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 (PrP(C)). 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.
authors.affiliation: Department of Biochemistry, Cambridge University, Tennis Court Road, Cambridge CB2 1QW, U.K. drb33@cam.ac.uk
authors.forename: D R
authors.initials: DR
authors.lastname: Brown
mesh_terms: D000409:Alanine / Q000737:chemistry*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001704:Biopolymers; D002478:Cells, Cultured; D002942:Circular Dichroism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000633:toxicity*; D011328:Prions / Q000737:chemistry / Q000235:genetics / Q000633:toxicity*; D017433:Protein Structure, Secondary; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators; D014633:Valine / Q000737:chemistry*
chemical_list: D001704:Biopolymers; D010446:Peptide Fragments; D011328:Prions; D014404:Tubulin; D050257:Tubulin Modulators; C082632:prion protein (106-126); D014633:Valine; D000409:Alanine