Computational investigation of the effect of reduced dynein velocity and reduced cargo diffusivity on slow axonal transport

Abstract

Contributions of three components of slow axonal transport (SAT) were studied using a computational model: the anterograde motor (kinesin)-driven component, the retrograde motor (dynein)-driven component, and the diffusion-driven component. The contribution of these three components of SAT was investigated in three different segments of the axon: the proximal portion, the central portion, and the distal portion of the axon. MAP1B protein was used as a model system to study SAT because there are published experimental data reporting MAP1B distribution along the axon length and average velocity of MAP1B transport in the axon. This allows the optimization approach to be used to find values of model kinetic constants that give the best fit with published experimental data. The effects of decreasing the value of cargo diffusivity on the diffusion-driven component of SAT and decreasing the value of dynein velocity on the retrograde motor-driven component of SAT were investigated. We found that for the case when protein diffusivity and dynein velocity are very small, it is possible to obtain an analytical solution to model equations. We found that, in this case, the protein concentration in the axon is uniform. This shows that anterograde motor-driven transport alone cannot simulate a variation of cargo concentration in the axon. Most proteins are non-uniformly distributed in axons. They may exhibit, for example, an increased concentration closer to the synapse. The need to reproduce a non-uniform distribution of protein concentration may explain why SAT is bidirectional (in addition to an anterograde component, it also contains a retrograde component).