Crowd Control: Effects of Physical Crowding on Cargo Movement in Healthy and Diseased Neurons

Abstract

High concentration of cytoskeletal filaments, organelles, and proteins along with the space constraints due to the axon’s narrow geometry lead inevitably to intracellular physical crowding along the axon of a neuron. Local cargo movement is essential for maintaining steady cargo transport in the axon, and this may be impeded by physical crowding. Molecular motors that mediate active transport share movement mechanisms that allow them to bypass physical crowding present on microtubule tracks. Many neurodegenerative diseases, irrespective of how they are initiated, show increased physical crowding owing to the greater number of stalled organelles and structural changes associated with the cytoskeleton. Increased physical crowding may be a significant factor in slowing cargo transport to synapses, contributing to disease progression and culminating in the dying back of the neuronal process. This review explores the idea that physical crowding can impede cargo movement along the neuronal process. We examine the sources of physical crowding and strategies used by molecular motors that might enable cargo to circumvent physically crowded locations. Finally, we describe sub-cellular changes in neurodegenerative diseases that may alter physical crowding and discuss the implications of such changes on cargo movement.

Cargo crowding, stationary clusters and dynamical reservoirs in axonal transport

“…Starting from such a jammed configuration, allowing for vesicle reversals dissolves the block, leading to a net current (Movie S2). This is consistent with the idea that allowing for reversals prevents vesicular crowding [34, 35]. Our simulation suggests that (i) the ability of moving vesicles to reverse is crucial to avoiding a permanently blocked state with no current and that (ii) side-stepping plays an important, but secondary, role in maintaining cargo flow along crowded neuronal processes.…”

“…However, even in the presence of such stalled vesicle clusters throughout the neuronal process, significant transport still takes place, suggesting that moving cargo employs mechanisms to navigate crowded locations. Prior studies have proposed that moving cargo can navigate obstacles by switching onto less crowded neighboring tracks or by reversing their direction of motion [34]. Additionally, results from the previous section also suggest a role for reversals in modulating cargo transport along the axonal process.…”

“…Two such motility characteristics that could regulate cargo crowding are sidestepping to another microtubule track and reversals. Several biophysical and modelling studies have proposed that moving cargo can navigate crowded locations through track switching, enabled by the association of cargo-bound motors with multiple microtubules [34]. Sidestepping provides a means of spatial relaxation of crowding, allowing vesicles to switch from more crowded to less crowded microtubule tracks, thereby maintaining cargo flow.…”

“…Reversals may also aid in avoiding crowded environments by allowing moving cargo to sample multiple microtubules, and redistributing cargo to avoid pile-ups at crowded locations [34, 35]. Reversals can reduce the frequency of vesicle-vesicle interactions at crowded locations by causing cargo to change their direction of motion.…”

“…S5 A-C). The absence of such an age dependent modulation in reversal rate in the tauopathy model may contribute to crowding and influence disease progression [34, 37, 38, 41, 42].…”