Direct Observation of Murine Prion Protein Replication in Vitro

被引:20
|
作者
Sang, Jason C. [1 ]
Meisl, Georg [1 ]
Thackray, Alana M. [2 ]
Hong, Liu [1 ,3 ]
Ponjavic, Aleks [1 ]
Knowles, Tuomas P. J. [1 ,4 ]
Bujdoso, Raymond [2 ]
Klenerman, David [1 ]
机构
[1] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England
[2] Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England
[3] Tsinghua Univ, Zhou Pei Yuan Ctr Appl Math, Beijing 100084, Peoples R China
[4] Univ Cambridge, Cavendish Lab, Cambridge CB3 0HE, England
基金
英国工程与自然科学研究理事会; 欧洲研究理事会; 英国生物技术与生命科学研究理事会; 英国国家替代、减少和改良动物研究中心;
关键词
PATHOLOGICAL ALPHA-SYNUCLEIN; AMYLOID FIBRIL GROWTH; TRANSGENIC MICE; DISEASE; AGGREGATION; NEURODEGENERATION; TRANSMISSION; MECHANISMS; REVEALS; OLIGOMERS;
D O I
10.1021/jacs.8b08311
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Prions are believed to propagate when an assembly of prion protein (PrP) enters a cell and replicates to produce two or more fibrils, leading to an exponential increase in PrP aggregate number with time. However, the molecular basis of this process has not yet been established in detail. Here, we use single-aggregate imaging to study fibril fragmentation and elongation of individual murine PrP aggregates from seeded aggregation in vitro. We found that PrP elongation occurs via a structural conversion from a PK-sensitive to PK-resistant conformer. Fibril fragmentation was found to be length-dependent and resulted in the formation of PK-sensitive fragments. Measurement of the rate constants for these processes also allowed us to predict a simple spreading model for aggregate propagation through the brain, assuming that doubling of the aggregate number is rate limiting. In contrast, while a-synuclein aggregated by the same mechanism, it showed significantly slower elongation and fragmentation rate constants than PrP, leading to much slower replication rate. Overall, our study shows that fibril elongation with fragmentation are key molecular processes in PrP and a-synuclein aggregate replication, an important concept in prion biology, and also establishes a simple framework to start to determine the main factors that control the rate of prion and prion-like spreading in animals.
引用
收藏
页码:14789 / 14798
页数:10
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