Inhibition of Kinesin-5, a Microtubule-Based Motor Protein, As a Strategy for Enhancing Regeneration of Adult Axons

Abstract

Developing neurons express a motor protein called kinesin-5 (also called kif11 or Eg5) which acts as a 'brake' on the advance of the microtubule array during axonal growth. Pharmacological inhibition of kinesin-5 causes the developing axon to grow at a faster rate, retract less and grow past cues that would otherwise cause it to turn. Here we demonstrate that kinesin-5 is also expressed in adult neurons, albeit at lower levels than during development. We hypothesized that inhibiting kinesin-5 might enable adult axons to regenerate better and to overcome repulsive molecules associated with injury. Using adult mouse dorsal root ganglion neurons, we found that anti-kinesin-5 drugs cause axons to grow faster and to cross with higher frequency onto inhibitory chondroitin sulfate proteoglycans. These effects may be due in part to changes in the efficiency of microtubule transport along the axonal shaft as well as enhanced microtubule entry into the distal tip of the axon. Effects observed with the drugs are further enhanced in some cases when they are used in combination with other treatments known to enhance axonal regeneration. Collectively, these results indicate that anti-kinesin-5 drugs may be a useful addition to the arsenal of tools used to treat nerve injury. © 2011 John Wiley & Sons A/S.