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首页> 外文期刊>BMC Biophysics >A discontinuous Galerkin model for fluorescence loss in photobleaching of intracellular polyglutamine protein aggregates
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A discontinuous Galerkin model for fluorescence loss in photobleaching of intracellular polyglutamine protein aggregates

机译：细胞内多谷氨酰胺蛋白聚集体光漂白过程中荧光损失的不连续Galerkin模型

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Intracellular phase separation and aggregation of proteins with extended poly-glutamine (polyQ) stretches are hallmarks of various age-associated neurodegenerative diseases. Progress in our understanding of such processes heavily relies on quantitative fluorescence imaging of suitably tagged proteins. Fluorescence loss in photobleaching (FLIP) is particularly well-suited to study the dynamics of protein aggregation in cellular models of Chorea Huntington and other polyQ diseases, as FLIP gives access to the full spatio-temporal profile of intensity changes in the cell geometry. In contrast to other methods, also dim aggregates become visible during time evolution of fluorescence loss in cellular compartments. However, methods for computational analysis of FLIP data are sparse, and transport models for estimation of transport and diffusion parameters from experimental FLIP sequences are missing. In this paper, we present a computational method for analysis of FLIP imaging experiments of intracellular polyglutamine protein aggregates also called inclusion bodies (IBs). By this method, we can determine the diffusion constant and nuclear membrane transport coefficients of polyQ proteins as well as the exchange rates between aggregates and the cytoplasm. Our method is based on a reaction-diffusion multi-compartment model defined on a mesh obtained by segmentation of the cell images from the FLIP sequence. The discontinuous Galerkin (DG) method is used for numerical implementation of our model in FEniCS, which greatly reduces the computing time. The method is applied to representative experimental FLIP sequences, and consistent estimates of all transport parameters are obtained. By directly estimating the transport parameters from live-cell image sequences using our new computational FLIP approach surprisingly fast exchange dynamics of mutant Huntingtin between cytoplasm and dim IBs could be revealed. This is likely relevant also for other polyQ diseases. Thus, our method allows for quantifying protein dynamics at different stages of the protein aggregation process in cellular models of neurodegeneration.
机译：具有扩展的聚谷氨酰胺（polyQ）延伸的蛋白质的细胞内相分离和聚集是各种与年龄相关的神经退行性疾病的标志。我们对此类过程的理解进展很大程度上取决于对适当标记的蛋白质进行定量荧光成像。光漂白（FLIP）中的荧光损失特别适合研究Chorea Huntington和其他polyQ疾病的细胞模型中蛋白质聚集的动力学，因为FLIP可以获取细胞几何结构强度变化的完整时空分布图。与其他方法相反，在细胞隔室中荧光损失的时间演变过程中，暗淡的聚集体也变得可见。但是，用于FLIP数据的计算分析的方法很少，并且缺少用于从实验FLIP序列估算运输和扩散参数的运输模型。在本文中，我们提出了一种计算方法，用于分析细胞内聚谷氨酰胺蛋白聚集体（也称为包涵体（IBs））的FLIP成像实验。通过这种方法，我们可以确定polyQ蛋白的扩散常数和核膜转运系数，以及聚集体和细胞质之间的交换速率。我们的方法基于在网格上定义的反应扩散多室模型，该模型是通过对FLIP序列中的细胞图像进行分割而获得的。不连续伽勒金（DG）方法用于FEniCS中我们模型的数值实现，这大大减少了计算时间。该方法应用于代表性的实验FLIP序列，并获得所有转运参数的一致估计。通过使用我们新的计算FLIP方法直接从活细胞图像序列中估算运输参数，可以令人惊讶地揭示出突变的Huntingtin在细胞质和昏暗的IB之间的快速交换动力学。这也可能与其他polyQ疾病有关。因此，我们的方法允许量化神经变性细胞模型中蛋白质聚集过程不同阶段的蛋白质动力学。

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