An Imaging and Systems Modeling Approach to Fibril Breakage Enables Prediction of Amyloid Behavior
An Imaging and Systems Modeling Approach to Fibril Breakage Enables Prediction of Amyloid Behavior
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DOI：
10.1016/j.bpj.2013.10.034
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发表时间：
2013-12-17
影响因子：
3.4
通讯作者：
Radford, Sheena E.
中科院分区：
文献类型：
--
作者：
Xue, Wei-Feng;Radford, Sheena E.
描述淀粉样蛋白原纤维的纳米级性质和动态组装和拆卸行为是使用淀粉样蛋白原纤维的材料性质的技术应用以及开发淀粉样蛋白相关疾病的治疗的关键。然而，对涉及这些非均相超分子系统的复杂过程的定量机理理解提出了尚未解决的挑战。在这里，我们开发了一种方法，能够解决的时间依赖性的原纤维颗粒浓度，长度分布，长度和位置依赖性的原纤维断裂率使用一个通用的数学框架结合来自原纤维长度分布的原子力显微镜分析的实验数据。通过应用于β 2-微球蛋白在体外恒定机械搅拌下的淀粉样蛋白组装，我们提出了纤维断裂和生长行为的完整描述，并证明了该方法在样品的纤维尺寸，纤维负载及其种子新淀粉样蛋白纤维生长的效率方面的预测能力。开发的方法提供了机会，以确定，量化和预测的过程和淀粉样蛋白组装的后果。
Delineating the nanoscale properties and the dynamic assembly and disassembly behaviors of amyloid fibrils is key for technological applications that use the material properties of amyloid fibrils, as well as for developing treatments of amyloid-associated disease. However, quantitative mechanistic understanding of the complex processes involving these heterogeneous supramolecular systems presents challenges that have yet to be resolved. Here, we develop an approach that is capable of resolving the time dependence of fibril particle concentration, length distribution, and length and position dependence of fibril fragmentation rates using a generic mathematical framework combined with experimental data derived from atomic force microscopy analysis of fibril length distributions. By application to amyloid assembly of beta(2)-microglobulin in vitro under constant mechanical stirring, we present a full description of the fibril-fragmentation and growth behavior, and demonstrate the predictive power of the approach in terms of the samples' fibril dimensions, fibril load, and their efficiency to seed the growth of new amyloid fibrils. The approach developed offers opportunities to determine, quantify, and predict the course and the consequences of amyloid assembly.