title: A kinetic model for amyloid formation in the prion diseases: importance of seeding.
abstract: The transmissible spongiform encephalopathies (TSEs) are neurodegenerative diseases characterized by amyloid formation in the brain. The major amyloid protein is the prion protein (PrP). PrP and the beta-amyloid protein of Alzheimer disease share a similar sequence that, in both cases, may be responsible for the initiation of protein aggregation in vivo. We report here that a peptide based on this sequence in PrP (PrP96-111M) forms amyloid fibrils. The existence of a kinetic barrier to amyloid formation by this peptide was demonstrated, suggesting that formation of an ordered nucleus is the rate-determining step for aggregation. Seeding was demonstrated to occur with PrP96-111M amyloid fibrils but not with amyloid fibrils of a related peptide. This effect is consistent with the proposal that the aggregation of PrP, which characterizes TSE, involves a nucleation event analogous to the seeding of a crystallization.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139.
authors.forename: J H
authors.initials: JH
authors.lastname: Come
authors.forename: P E
authors.initials: PE
authors.lastname: Fraser
authors.forename: P T
authors.initials: PT
authors.lastname: Lansbury
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D017096:Prion Diseases / Q000378:metabolism*; D011328:Prions / Q000378:metabolism; D013816:Thermodynamics; D014779:Virus Replication
chemical_list: D000682:Amyloid; D010446:Peptide Fragments; D011328:Prions