The shape and function of an axon is dependent on its cytoskeleton, including microtubules, neurofilaments and actin. Neurofilaments accumulate abnormally in axons in many neurological disorders including ALS. In many situations, an early event of such accumulation is a striking radial segregation of microtubules and neurofilaments. This phenomenon has been observed for over 30 years now, but the underlying mechanism is still poorly understood. To address this problem, we developed a stochastic multiscale model for the cross-sectional cytoskeleton dynamics in an axon. The model successfully explained the cytoskeletal segregation and generated testable predictions. Based on the insights obtained using the stochastic model, we extracted a heuristic nonlocal PDE model that has led to further insights into this problem through mathematical analysis and fast computation. These modeling efforts have motivated new experiments in Dr. Anthony Brown’s lab from Dept. of Neuroscience at the Ohio State University.