Dynein dysfunction prevents maintenance of high concentrations of slow axonal transport cargos at the axon terminal

Abstract

We use two different models to simulate bidirectional transport in an axon: an anterograde-retrograde model and a full slow transport model. Our goal is to investigate what the models would predict if 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 of Charcot-Marie-Tooth disease. We attempt to understand why this happens. Indeed, dynein is a retrograde motor, and its mutations should not directly influence anterograde transport toward the axon terminal. Our modeling results unexpectedly predict that slow axonal transport fails to transport cargos against their concentration gradient if the dynein motor fails. The reason is the inability of the kinesin-only transport model to know what cargo concentration must be maintained at the axon tip because of the absence of a retrograde motor. Perturbation analysis for the case when the retrograde motor velocity becomes close to zero predicts uniform cargo distributions along the axon. A neuron may attempt to increase the cargo concentration in the terminal by increasing the somatic cargo concentration. This may lead to other problems, such as the formation of Lewy bodies in the case of alpha-synuclein. 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.