Department of Biology, University of Houston, Houston, TX, USA.
School of Mathematics and Statistics, University of St Andrews, St Andrews KY16 9SS, UK.
Proc Biol Sci. 2023 Jul 12;290(2002):20230905. doi: 10.1098/rspb.2023.0905. Epub 2023 Jul 5.
Prion and prion-like molecules are a type of self-replicating aggregate protein that have been implicated in a variety of neurodegenerative diseases. Over recent decades, the molecular dynamics of prions have been characterized both empirically and through mathematical models, providing insights into the epidemiology of prion diseases and the impact of prions on the evolution of cellular processes. At the same time, a variety of evidence indicates that prions are themselves capable of a form of evolution, in which changes to their structure that impact their rate of growth or fragmentation are replicated, making such changes subject to natural selection. Here we study the role of such selection in shaping the characteristics of prions under the nucleated polymerization model (NPM). We show that fragmentation rates evolve to an evolutionary stable value which balances rapid reproduction of aggregates with the need to produce stable polymers. We further show that this evolved fragmentation rate differs in general from the rate that optimizes transmission between cells. We find that under the NPM, prions that are both evolutionary stable and optimized for transmission have a characteristic length of three times the critical length below which they become unstable. Finally, we study the dynamics of inter-cellular competition between strains, and show that the eco-evolutionary trade-off between intra- and inter-cellular competition favours coexistence.
朊病毒和类朊病毒分子是一种自我复制的聚集蛋白，与多种神经退行性疾病有关。近几十年来，通过经验和数学模型对朊病毒的分子动力学进行了特征描述，为了解朊病毒疾病的流行病学以及朊病毒对细胞过程进化的影响提供了线索。与此同时，各种证据表明，朊病毒本身就具有一种进化形式，在这种形式中，影响其生长或断裂速度的结构变化会被复制，从而使这些变化受到自然选择的影响。在这里，我们在有核聚合模型（NPM）下研究了这种选择在塑造朊病毒特征中的作用。我们表明，断裂速率进化到一个平衡了聚集体快速繁殖和产生稳定聚合物的需要的稳定值。我们进一步表明，这种进化的断裂速率通常与优化细胞间传递的速率不同。我们发现，在 NPM 下，既具有进化稳定性又优化了传递的朊病毒具有一个特征长度，是其变得不稳定的临界长度的三倍。最后，我们研究了细胞间竞争的动态，结果表明，细胞内和细胞间竞争之间的生态进化权衡有利于共存。
