Actomyosin-II facilitates long-range retrograde transport of large cargoes by controlling axonal radial contractility

Most mammalian neurons have a narrow axon, which constrains the passage of large cargoes such as autophagosome as they can be larger than the axon diameter. Variations in tension must therefore occur radially to facilitate changes in axonal diameter and ensure efficient axoplasmic trafficking. Here, we reveal that the transit of diverse large membrane-bound cargoes causes an acute, albeit transient, radial expansion of the axonal diameter, which is immediately restored by constricting forces. We demonstrate that non-muscle myosin II (NM-II) forms ~200 nm periodic structures, which associate with axonal F-actin rings. Inhibition of NM-II activity with blebbistatin significantly increases axon diameter without affecting the periodicity of either the F-actin rings or NM-II. This sustained radial expansion significantly affects the trafficking speed, directionality, and reduces the overall efficiency of long-range retrograde axonal cargoes, eventually leading to focal axon swelling and cargo accumulation, which are hallmarks of axonal degeneration.