Activation of Sarm1 produces cADPR to increase intra-axonal calcium and promote axon degeneration in CIPN

Li, Y.; Pazyra-Murphy, M. F.; Avizonis, D.; De Sa Tavares Russo, M.; Tang, S.; Bergholz, J. S.; Jiang, T.; Zhao, J. J.; Zhu, J.; Ko, K. W.; Milbrandt, J.; DiAntonio, A.; Segal, R.

doi:10.1101/2021.04.15.440024

bioRxiv · 10.1101/2021.04.15.440024

Activation of Sarm1 produces cADPR to increase intra-axonal calcium and promote axon degeneration in CIPN

Li, Y.·Pazyra-Murphy, M. F.·Avizonis, D.·De Sa Tavares Russo, M.·Tang, S.·Bergholz, J. S.·Jiang, T.·Zhao, J. J.·Zhu, J.·Ko, K. W.·Milbrandt, J.·DiAntonio, A.·Segal, R.

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Abstract

Cancer patients frequently develop chemotherapy-induced peripheral neuropathy (CIPN), a painful and long-lasting disorder with profound somatosensory deficits. There are no effective therapies to prevent or treat this disorder. Pathologically, CIPN is characterized by a "dying-back" axonopathy that begins at intra-epidermal nerve terminals of sensory neurons and progresses in a retrograde fashion. Calcium dysregulation constitutes a critical event in CIPN, but it is not known how chemotherapies such as paclitaxel alter intra-axonal calcium and cause degeneration. Here, we demonstrate that paclitaxel triggers Sarm1-dependent cADPR production in distal axons, promoting intra-axonal calcium flux from both intracellular and extracellular calcium stores. Genetic or pharmacologic antagonists of cADPR signaling prevent paclitaxel-induced axon degeneration and allodynia symptoms, without mitigating the anti-neoplastic efficacy of paclitaxel. Our data demonstrate that cADPR is a calcium modulating factor that promotes paclitaxel-induced axon degeneration and suggest that targeting cADPR signaling provides a potential therapeutic approach for treating CIPN. HIGHLIGHTSO_LIPaclitaxel induces intra-axonal calcium flux C_LIO_LISarm1-dependent cADPR production promotes axonal calcium elevation and degeneration C_LIO_LIAntagonizing cADPR signaling pathway protects against paclitaxel-induced peripheral neuropathy in vitro and in vivo C_LI

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Li, Y., Pazyra-Murphy, M. F., Avizonis, D., De Sa Tavares Russo, M., Tang, S., Bergholz, J. S., Jiang, T., Zhao, J. J., Zhu, J., Ko, K. W., Milbrandt, J., DiAntonio, A., Segal, R.. 2021-04-15. Activation of Sarm1 produces cADPR to increase intra-axonal calcium and promote axon degeneration in CIPN. https://doi.org/10.1101/2021.04.15.440024

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