Quantifying the kinetic parameters of prion replication

被引:178
作者
Masel, J
Jansen, VAA
Nowak, MA
机构
[1] Univ Oxford, Dept Zool, Wellcome Trust Ctr Epidemiol Infect Dis, Oxford OX1 3PS, England
[2] Inst Adv Study, Princeton, NJ 08540 USA
基金
英国惠康基金;
关键词
prion diseases; replication mechanism; nucleated polymerisation; mathematical model;
D O I
10.1016/S0301-4622(99)00016-2
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mechanism of protein-only prion replication is controversial. A detailed mathematical model of prion replication by nucleated polymerisation is developed, and its parameters are estimated from published data. PrP-res decay is around mio orders of magnitude slower than PrP-sen decay, a plausible ratio of two parameters estimated from very different experiments. By varying the polymer breakage rate, we reveal that systems of short polymers grow the fastest. Drugs which break polymers could therefore accelerate disease progression. Growth in PrP-res seems slower than growth in infectious titre. This can be explained either by a novel hypothesis concerning inoculum clearance from a newly infected brain, or by the faster growth of compartments containing smaller polymers. The existence of compartments can also explain why prion growth sometimes reaches a plateau. Published kinetic data are all compatible with our mathematical model, so the nucleated polymerisation hypothesis cannot be ruled out on dynamic grounds. (C) 1999 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:139 / 152
页数:14
相关论文
共 60 条
[1]   Prion research: the next frontiers [J].
Aguzzi, A ;
Weissmann, C .
NATURE, 1997, 389 (6653) :795-798
[2]  
ANDERSON R M, 1991
[3]   COPURIFICATION OF SP33-37 AND SCRAPIE AGENT FROM HAMSTER BRAIN PRIOR TO DETECTABLE HISTOPATHOLOGY AND CLINICAL-DISEASE [J].
BOLTON, DC ;
RUDELLI, RD ;
CURRIE, JR ;
BENDHEIM, PE .
JOURNAL OF GENERAL VIROLOGY, 1991, 72 :2905-2913
[4]   Prion distribution in hamster lung and brain following intraperitoneal inoculation [J].
Bolton, DC .
JOURNAL OF GENERAL VIROLOGY, 1998, 79 :2557-2562
[5]   SCRAPIE AND CELLULAR PRION PROTEINS DIFFER IN THEIR KINETICS OF SYNTHESIS AND TOPOLOGY IN CULTURED-CELLS [J].
BORCHELT, DR ;
SCOTT, M ;
TARABOULOS, A ;
STAHL, N ;
PRUSINER, SB .
JOURNAL OF CELL BIOLOGY, 1990, 110 (03) :743-752
[6]   MICE DEVOID OF PRP ARE RESISTANT TO SCRAPIE [J].
BUELER, H ;
AGUZZI, A ;
SAILER, A ;
GREINER, RA ;
AUTENRIED, P ;
AGUET, M ;
WEISSMANN, C .
CELL, 1993, 73 (07) :1339-1347
[7]  
BUELER H, 1994, MOL MED, V1, P19
[8]   SCRAPIE-INFECTED MURINE NEURO-BLASTOMA CELLS PRODUCE PROTEASE-RESISTANT PRION PROTEINS [J].
BUTLER, DA ;
SCOTT, MRD ;
BOCKMAN, JM ;
BORCHELT, DR ;
TARABOULOS, A ;
HSIAO, KK ;
KINGSBURY, DT ;
PRUSINER, SB .
JOURNAL OF VIROLOGY, 1988, 62 (05) :1558-1564
[9]   PRION PROTEIN-BIOSYNTHESIS IN SCRAPIE-INFECTED AND UNINFECTED NEURO-BLASTOMA CELLS [J].
CAUGHEY, B ;
RACE, RE ;
ERNST, D ;
BUCHMEIER, MJ ;
CHESEBRO, B .
JOURNAL OF VIROLOGY, 1989, 63 (01) :175-181
[10]   Prion protein and the transmissible spongiform encephalopathies [J].
Caughey, B ;
Chesebro, B .
TRENDS IN CELL BIOLOGY, 1997, 7 (02) :56-62