A Kinetic Model for Amyloid Formation in the Prion Diseases: Importance of Seeding

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 90; no. 13; pp. 5959 - 5963
• Main Authors: Come, Jon H., Fraser, Paul E., Lansbury, Peter T.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 01.07.1993; National Acad Sciences; National Academy of Sciences
• Subjects: Aggregation; Alzheimer Disease - metabolism; Amino Acid Sequence; Amyloid - biosynthesis; Amyloid - chemistry; Amyloids; Biochemistry; Biological and medical sciences; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease; Humans; Kinetics; Medical sciences; Models, Biological; Molecular Sequence Data; Neurology; Nucleation; Peptide Fragments - chemistry; Prion diseases; Prion Diseases - metabolism; Prions; Prions - metabolism; Proteins; Seeding; Solar fibrils; Thermodynamics; Virus Replication; Nervous system diseases; Alzheimer disease; Mechanism; Infection; Aggregation; Conserved sequence; Peptide fragment; β Amyloid protein; Viral disease; Infectivity; Degenerative disease; Prion; Kinetics; Prion protein; Creutzfeldt Jakob disease; Fibril
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.13.5959

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 β-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.