体内长度分布作为病理性蛋白质聚集的机制指纹
In Vivo Length Distributions as Mechanistic Fingerprints of Pathological Protein Aggregation
- Yusuf Hamied Department of Chemistry, University of Cambridge（剑桥大学尤素福·哈米德化学系）
- UK Dementia Research Institute at University of Cambridge（剑桥大学英国痴呆症研究所）
机构由 AI 辅助整理，请以论文原文为准。
AI总结：
本文建立数学模型，利用体内聚集体长度分布的几何衰减率推断伸长与清除的平衡，从而无需纵向测量即可从人体组织揭示病理性蛋白质聚集的微观机制。
AI中文摘要：
现代成像技术能够在死后人体样本中分辨单个病理性蛋白质聚集体，提供传统批量方法无法获得的聚集体尺寸分布的详细测量。这些分布代表了产生所观察病理的微观过程的机制指纹，但提取这些机制信息需要定量的理论框架。在此，我们开发了解释活体系统中聚集体长度分布所需的数学工具，在活体系统中，聚集体生长与主动清除相互竞争。我们表明，在一类模型中，足够大的聚集体的长度分布趋近于几何衰减。关键在于，衰减率由聚集体伸长与清除之间的平衡决定，从而从单个时间点测量中直接定量读出这些竞争过程。这使得无需纵向测量聚集体动力学即可对健康和患病人体样本进行机制比较。我们进一步分析了额外的聚集和清除过程如何改变观察到的长度分布。总之，这些结果建立了数学基础和工具，以利用聚集体长度分布作为从人体组织直接推断微观聚集动力学的实验可行途径。
英文摘要：
Modern imaging techniques can resolve individual pathological protein aggregates in postmortem human samples, providing detailed measurements of aggregate size distributions that are inaccessible with conventional bulk approaches. These distributions represent mechanistic fingerprints of the microscopic processes that generated the observed pathology, but extracting this mechanistic information requires a quantitative theoretical framework. Here, we develop the mathematical tools needed to interpret aggregate length distributions in living systems, where aggregate growth competes with active removal. We show that, across a class of models, the length distribution of sufficiently large aggregates approaches a geometric decay. Crucially, the decay rate is determined by the balance between aggregate elongation and removal, providing a direct quantitative readout of these competing processes from a single time point measurement. This enables mechanistic comparisons between healthy and diseased human samples without requiring longitudinal measurements of aggregate dynamics. We further analyse how additional aggregation and removal processes modify the observed length distributions. Together, these results establish the mathematical foundations and tools to use aggregate length distributions as an experimentally accessible route for inferring microscopic aggregation dynamics directly from human tissue.
