Dual Specificity Phosphatases Support Axon Plasticity and Viability

In peripheral neuropathies, axonal degeneration (AxD) impairs the prognosis for recovery. Here, we describe a role for dual specificity phosphatases (DUSPs; MAP kinase phosphatases, MKPs), in supporting autonomous axon plasticity and viability. Both DUSPs 1 and 4 were identified within intact or axotomized sensory neurons. Knockdown of DUSP 1 or 4 independently or combined impaired neurite outgrowth in adult dissociated sensory neurons. Furthermore, adult sensory neurons with DUSP knockdown were rendered sensitive to axonopathy in vitro following exposure to low, subtoxic TrpV1 (transient receptor potential cation channel subfamily V member 1) activation by capsaicin, an intervention normally supportive of growth. This was not prevented by concurrent DLK (dual leucine zipper kinase) knockdown. Ex vivo neurofilament dissolution was heightened by DUSP inhibition within explanted nerves. In vivo DUSP knockdown or inhibition was associated with more rapid loss of motor axon excitability. The addition of SARM1 (sterile alpha and TIR motif containing 1) siRNA abrogated DUSP1 and 4 mediated loss of excitability. DUSP knockdown accelerated neurofilament breakdown and there was earlier morphological evidence of myelinated axon degeneration distal to axotomy. Taken together, the findings identify a key role for DUSPs in supporting axon plasticity and survival.