Kuznetsov Ivan A, Kuznetsov Andrey V
a Perelman School of Medicine , University of Pennsylvania , Philadelphia , PA , USA.
b Department of Bioengineering , University of Pennsylvania , Philadelphia , PA , USA.
Comput Methods Biomech Biomed Engin. 2019 Jan;22(1):71-83. doi: 10.1080/10255842.2018.1534233. Epub 2018 Dec 24.
Evaluating the sensitivity of biological models to various model parameters is a critical step towards advancing our understanding of biological systems. In this paper, we investigated sensitivity coefficients for a model simulating transport of tau protein along the axon. This is an important problem due to the relevance of tau transport and agglomeration to Alzheimer's disease and other tauopathies, such as some forms of parkinsonism. The sensitivity coefficients that we obtained characterize how strongly three observables (the tau concentration, average tau velocity, and the percentage of tau bound to microtubules) depend on model parameters. The fact that the observables strongly depend on a parameter characterizing tau transition from the retrograde to the anterograde kinetic states suggests the importance of motor-driven transport of tau. The observables are sensitive to kinetic constants characterizing tau concentration in the free (cytosolic) state only at small distances from the soma. Cytosolic tau can only be transported by diffusion, suggesting that diffusion-driven transport of tau only plays a role in the proximal axon. Our analysis also shows the location in the axon in which an observable has the greatest sensitivity to a certain parameter. For most parameters, this location is in the proximal axon. This could be useful for designing an experiment aimed at determining the value of this parameter. We also analyzed sensitivity of the average tau velocity, the total tau concentration, and the percentage of microtubule-bound tau to cytosolic diffusivity of tau and diffusivity of bound tau along the MT lattice. The model predicts that at small distances from the soma the effect of these two diffusion processes is comparable.
评估生物模型对各种模型参数的敏感性是增进我们对生物系统理解的关键一步。在本文中，我们研究了一个模拟tau蛋白沿轴突运输的模型的敏感性系数。由于tau蛋白运输和聚集与阿尔茨海默病及其他tau蛋白病（如某些形式的帕金森症）相关，这是一个重要问题。我们获得的敏感性系数表征了三个可观测值（tau蛋白浓度、平均tau蛋白速度以及与微管结合的tau蛋白百分比）对模型参数的依赖程度。可观测值强烈依赖于一个表征tau蛋白从逆行动力学状态向前行动力学状态转变的参数，这一事实表明了tau蛋白的运动驱动运输的重要性。这些可观测值仅在距胞体较小距离处对表征游离（胞质）状态下tau蛋白浓度的动力学常数敏感。胞质中的tau蛋白只能通过扩散运输，这表明扩散驱动的tau蛋白运输仅在轴突近端起作用。我们的分析还显示了轴突中一个可观测值对某个参数具有最大敏感性的位置。对于大多数参数而言，这个位置在轴突近端。这对于设计旨在确定该参数值的实验可能是有用的。我们还分析了平均tau蛋白速度、总tau蛋白浓度以及与微管结合的tau蛋白百分比对tau蛋白的胞质扩散系数以及沿微管晶格的结合tau蛋白扩散系数的敏感性。该模型预测，在距胞体较小距离处，这两个扩散过程的影响相当。
