Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104.
Department of Mechanical and Aerospace Engineering, North Carolina State University, Raleigh, NC 27695-7910.
J Biomech Eng. 2023 Jul 1;145(7). doi: 10.1115/1.4056915.
Here, we report computational studies of bidirectional transport in an axon, specifically focusing on predictions when the retrograde motor becomes dysfunctional. We are motivated by reports that mutations in dynein-encoding genes can cause diseases associated with peripheral motor and sensory neurons, such as type 2O Charcot-Marie-Tooth disease. We use two different models to simulate bidirectional transport in an axon: an anterograde-retrograde model, which neglects passive transport by diffusion in the cytosol, and a full slow transport model, which includes passive transport by diffusion in the cytosol. As dynein is a retrograde motor, its dysfunction should not directly influence anterograde transport. However, our modeling results unexpectedly predict that slow axonal transport fails to transport cargos against their concentration gradient without dynein. The reason is the lack of a physical mechanism for the reverse information flow from the axon terminal, which is required so that the cargo concentration at the terminal could influence the cargo concentration distribution in the axon. Mathematically speaking, to achieve a prescribed concentration at the terminal, equations governing cargo transport must allow for the imposition of a boundary condition postulating the cargo concentration at the terminal. Perturbation analysis for the case when the retrograde motor velocity becomes close to zero predicts uniform cargo distributions along the axon. The obtained results explain why slow axonal transport must be bidirectional to allow for the maintenance of concentration gradients along the axon length. Our result is limited to small cargo diffusivity, which is a reasonable assumption for many slow axonal transport cargos (such as cytosolic and cytoskeletal proteins, neurofilaments, actin, and microtubules) which are transported as large multiprotein complexes or polymers.
在这里，我们报告了轴突内双向运输的计算研究，特别是关注当逆行运动器功能失调时的预测。我们的研究动机是报道称，动力蛋白编码基因的突变会导致与周围运动和感觉神经元相关的疾病，如 2O 型 Charcot-Marie-Tooth 病。我们使用两种不同的模型来模拟轴突内的双向运输：一个是顺行-逆行模型，它忽略了细胞质中扩散引起的被动运输；另一个是完整的缓慢运输模型，它包括细胞质中扩散引起的被动运输。由于动力蛋白是一种逆行运动器，它的功能障碍不应该直接影响顺行运输。然而，我们的建模结果出人意料地预测，如果没有动力蛋白，缓慢轴突运输将无法在逆浓度梯度的情况下运输货物。原因是缺乏从轴突末端反向信息流的物理机制，这是必需的，以便末端的货物浓度可以影响轴突内的货物浓度分布。从数学上讲，为了在末端达到规定的浓度，控制货物运输的方程必须允许施加一个边界条件，假设末端的货物浓度。当逆行运动器速度接近零时的摄动分析预测了沿轴突的均匀货物分布。所得到的结果解释了为什么缓慢轴突运输必须是双向的，以便允许在轴突长度上维持浓度梯度。我们的结果仅限于小货物扩散性，这对于许多缓慢轴突运输货物（如细胞质和细胞骨架蛋白、神经丝、肌动蛋白和微管）是合理的假设，这些货物作为大的多蛋白复合物或聚合物进行运输。
