Studies of the amyloid fibril formation of the prion peptides

• Main Authors: Yen-Li Lee, 李彥莉
• Other Authors: 林聖賢
• Format: Others
• Language: en_US
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/60465710606825137242

碩士 === 國立臺灣大學 === 化學研究所 === 93 === Abstract Prion diseases comprise a group of neurodegenerative transmissible spongiform encephalopathies (TSE). The epidemic of mad cow disease happened in England in 1990s and its recent spread to humans have received broad attention all over the world. Although the pathogenesis of the prion diseases is not completely disclosed so far, it has been known that the drastic structural transition from native PrPC to abnormal pathogenic PrPSc leads to the prion diseases. However, the transmission of the prion diseases was found to be species-specific. In order to study the species barrier of the prion transmission, prion peptides corresponding to hamster PrP sequence 108 to 144 and mouse PrP sequence 107 to 143 were used as a model system. We established a system to quantify the transmission barrier and to examine how sequence difference affects the transmission efficiency. The transmission barrier between mouse and hamster prion peptides was found to be about 5 times higher than the homologous transmission. In addition, residue 139 plays a critical role in the seeding specificity. The energy barrier prevents mouse from infection with hamster fibrils can be abolished by a single mutation at residue 139 with isoleucine substituted for methionine in the hamster fibrils. However, an I139→M mutation in the mouse fibrils still has strong seeding barrier to the hamster prion peptide while the same fibrils can induce the fibrillization of the mouse prion peptide easily. In this case, the homology within the region spanning residue 109-112 turns into the principal factor for determining the seeding specificity of the prion fibrils. Moreover, the human prion gene presents a polymorphism at the codon 129, resulting in either methionine or valine. The previous studies showed that this polymorphism has a profound effect on the susceptibility and pathological phenotype of the human prion disease. In this study, we also evaluated the influence of this polymorphism in the transmission efficiency between bovine and human using the same peptide model system. Our finding suggested that the methionine homozygote has higher susceptibility to the bovine PrP fibrils whereas the Val homozygote is resistant to the TSE infection. Finally, our studies in the fibrillization kinetics of the human prion peptides showed that the co-existence of the huPrP129MM and huPrP129VV peptides would retard the nucleation rate compared with the homozygous ones. The interference effect indicated that the heterozygote disfavored amyloid formation and explained why most of the sCJD patients are 129 homozygotes at the codon 129.