Inhibition of kinesin-5 improves regeneration of injured axons by a novel microtubule-based mechanism

Abstract

Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concerns that abnormally stabilizing microtubules may have only limited benefits for regeneration, while at the same time may be detrimental to the normal work that microtubules perform for the axon. Kinesin-5 (also called kif11 or Eg5), a molecular motor protein best known for its crucial role in mitosis, acts as a brake on microtubule movements by other motor proteins in the axon. Drugs that inhibit kinesin-5, originally developed to treat cancer, result in greater mobility of microtubules in the axon and an overall shift in the forces on the microtubule array. As a result, the axon grows faster, retracts less, and more readily enters environments that are inhibitory to axonal regeneration. Thus, drugs that inhibit kinesin-5 offer a novel microtubule-based means to boost axonal regeneration without the concerns that accompany abnormal stabilization of the microtubule array. Even so, inhibiting kinesin-5 is not without its own caveats, such as potential problems with navigation of the regenerating axon to its target, as well as morphological effects on dendrites that could affect learning and memory if the drugs reach the brain.

Keywords: Eg5; axon; kinesin-5; microtubule; molecular motor protein; monastrol; regeneration.

Figure 1

Kinesin-5 is a brake on microtubule movements in the axon. Shown is a schematic model for how molecular motors regulate micro-tubule movements in the axon. In the axon, long microtubules are di-rected with their plus ends distal to the cell body. Cytoplasmic dynein transports short microtubules in both directions in the axon, with the short microtubules moving either forward or backward depending on their polarity orientation (Baas and Mozgova, 2012). Kinesin-5 acts as a brake that impedes microtubule transport and sliding. When kine-sin-5 is pharmacologically inhibited by monastrol, a greater number of short microtubules become mobile. The balance of forces on the lon-ger microtubules changes as well, enabling greater invasiveness of the long microtubules into the growth cone.

Figure 2

Kinesin-5 inhibition enables injured adult axons to regenerate better. Kinesin-5 inhibition by monastrol re-sults in a faster growing axon, due to greater mobility within the microtubule array, as well as an enhanced capacity of the axon to cross over a boundary onto a chondroitin sulfate proteogly-cans (CSPG) (inhibitory) substrate. Crossing onto CSPGs is enhanced if the monastrol treatment is coupled with an enzyme treatment that partially digests the CSPGs.