Promotion of Functional Nerve Regeneration by Inhibition of Microtubule Detyrosination

Abstract

Peripheral nerve regeneration often remains incomplete, due to an insufficient growth rate of injured axons. Transgenic mice with sustained GSK3 activity showed markedly accelerated nerve regeneration upon injury. Here, we identified the molecular mechanism underlying this phenomenon and provide a novel therapeutic principle for promoting nerve repair. Analysis of transgenic mice revealed a dependence on overall GSK3 activity and reduction of microtubule detyrosination in axonal tips. Pharmacological inhibition of detyrosination by parthenolide fully mimicked this axon growth promotion in wild-type mice. Strikingly, local or systemic treatment with parthenolidein vivomarkedly accelerated axon regeneration and functional recovery. Thus, pharmacological inhibition of microtubule detyrosination may be a novel, clinically suitable strategy for nerve repair with potential relevance for human patients.