Dual Specificity Phosphatases Support Axon Plasticity and Viability
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Dual Specificity Phosphatases Support Axon Plasticity and Viability Ambika Chandrasekhar 1 & Prashanth Komirishetty 1 & Aparna Areti 1 & Anand Krishnan 1,2 & Douglas W. Zochodne 1 Received: 3 May 2020 / Accepted: 5 September 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords Axonal degeneration . Dual specificity phosphatases . MAP kinase phosphatases
Adult axon viability is a crucial factor in deciding whether a devastating axonopathy results from inflammatory polyneuropathies, chemotherapeutic treatment, or an array of disorders that target peripheral nerves [8]. Over the last decade, the discovery of intrinsic molecular programs that bear upon how axons fare or resist degeneration has offered new targets. These are new approaches toward preventing “irreversible” axonal degeneration (AxD). Rather than a passive process secondary to the separation of the axon from the cell body, AxD (also called Wallerian degeneration if it follows nerve transection) is now recognized as an active and complex molecular cascade with a number of distinct molecular players, briefly Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12035-020-02119-6) contains supplementary material, which is available to authorized users. * Douglas W. Zochodne [email protected] 1
Neuroscience and Mental Health Institute and Division of Neurology, Department of Medicine, University of Alberta, 7-132A Clinical Sciences Building, 11350-83 Ave, Edmonton, AB T6G 2G3, Canada
2
Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, Canada
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