The slow axonal transport of alpha‐synuclein—mechanistic commonalities amongst diverse cytosolic cargoes

Abstract

Slow axonal transport conveys perikaryally-synthesized cytosolic proteins in a rate-class called Slow Component-b (SCb). One such protein--α-synuclein--is largely conveyed in SCb, and is also a key player in a group of neurodegenerative diseases called synucleinopathies. Axonal transport defects of α-synuclein have been hypothesized to play a role in synucleinopathies, but mechanisms moving α-synuclein in slow axonal transport are unclear. Here we use a recently developed model-system in our laboratory to visualize the slow transport of α-synuclein, comparing it to another SCb protein synapsin. Despite differences inbiological properties and overall-solubility in axons, the anterograde transport of both SCb proteins was strikingly similar, suggesting commonalities in slow axonal transport mechanisms of seemingly diverse cytosolic cargoes. The data support a model where SCb proteins dynamically organize into 'transport-competent' complexes that are conveyed via transient associations with other persistently-moving cargoes ("mobile-units"). The identity of the latter is yet unknown. Visualizing normal α-synuclein transport may also open the door to studies of α-synuclein transport in pathologic states.