The interplay of active and passive mechanisms in slow axonal transport

A combination of intermittent active movement of transient aggregates and a paused state that intervenes between periods of active transport has been proposed to underlie the slow, directed transport of soluble proteins in axons. A component of passive diffusion in the axoplasm may also contribute to slow axonal transport, although quantitative estimates of the relative contributions of diffusive and active movement in the slow transport of a soluble protein, and in particular how they might vary across developmental stages, are lacking. Here, we propose and study a model for slow axonal transport, addressing data from bleach recovery measurements on a small, soluble, protein, choline acetyltransferase, in thin axons of the lateral chordotonal (lch5) sensory neurons of Drosophila. Choline acetyltransferase is mainly present in soluble form in the axon and catalyzes the acetylation of choline at the synapse. It does not form particulate structures in axons and moves at rates characteristic of slow component b (≈ 1-10 mm/day or 0.01-0.1 μm/s). Using our model, which incorporates active transport with paused and/or diffusive states, we predict bleach recovery, transport rates, and cargo trajectories obtained through kymographs, comparing these with experimental observations at different developmental stages. We show that changes in the diffusive fraction of cargo during these developmental stages dominate bleach recovery and that a combination of active motion with a paused state alone cannot reproduce the data. We compared predictions of the model with results from photoactivation experiments. The importance of the diffusive state in reproducing the bleach recovery signal in the slow axonal transport of small soluble proteins is our central result.