A mathematical model of the dynamics of prion aggregates with chaperone-mediated fragmentation.
A mathematical model of the dynamics of prion aggregates with chaperone-mediated fragmentation.
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DOI：
10.1007/s00285-015-0921-0
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发表时间：
2016-05
影响因子：
1.9
通讯作者：
Sindi SS
中科院分区：
文献类型：
--
作者：
Davis JK;Sindi SS
朊病毒是最常见的与哺乳动物致命的神经退行性疾病有关的蛋白质，但也是酵母中许多无害的遗传表型的原因。当蛋白质的错误折叠形式出现时，这些状态就会出现，而不是被细胞质量控制机制去除，而是持续存在。错误折叠的朊病毒蛋白形成聚集体，并能够通过两种形式之间的直接相互作用将正常折叠的蛋白转化为错误折叠状态。朊病毒聚集体动力学的主要数学模型是核聚合模型（NPM），它只考虑正常蛋白质和聚集体的动力学。然而，对于酵母朊病毒的分子伴侣Hsp 104是必不可少的朊病毒繁殖。此外，虽然哺乳动物不表达Hsp 104，但实验测定显示Hsp 104也与哺乳动物朊病毒聚集体相互作用。在这项研究中，我们推广的NPM占分子伴侣和开发我们所谓的酶限制成核聚合模型（ELNPM）。我们讨论了我们的模型的解的存在性，唯一性和稳定性，并证明了NPM代表了我们的模型的准稳态约化。我们验证ELNPM的酵母朊病毒PSI，不能支持的NPM的实验结果证明协议。最后，我们证明，与NPM相比，ELNPM允许多种朊病毒株的共存。本文的在线版本（doi：10.1007/s 00285 -015-0921-0）包含补充材料，可供授权用户使用。
Prions are proteins most commonly associated with fatal neurodegenerative diseases in mammals but are also responsible for a number of harmless heritable phenotypes in yeast. These states arise when a misfolded form of a protein appears and, rather than be removed by cellular quality control mechanisms, persists. The misfolded prion protein forms aggregates and is capable of converting normally folded protein to the misfolded state through direct interaction between the two forms. The dominant mathematical model for prion aggregate dynamics has been the nucleated polymerization model (NPM) which considers the dynamics of only the normal protein and the aggregates. However, for yeast prions the molecular chaperone Hsp104 is essential for prion propagation. Further, although mammals do not express Hsp104, experimental assays have shown Hsp104 also interacts with mammalian prion aggregates. In this study, we generalize the NPM to account for molecular chaperones and develop what we call the enzyme-limited nucleated polymerization model (ELNPM). We discuss existence, uniqueness and stability of solutions to our model and demonstrate that the NPM represents a quasi-steady-state reduction of our model. We validate the ELNPM by demonstrating agreement with experimental results on the yeast prion PSI that could not be supported by the NPM. Finally, we demonstrate that, in contrast to the NPM, the ELNPM permits the coexistence of multiple prion strains. The online version of this article (doi:10.1007/s00285-015-0921-0) contains supplementary material, which is available to authorized users.