Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN

  • J Cell Biol. 2022 Feb 7;221(2):e202106080. doi: 10.1083/jcb.202106080.
Yihang Li  1  2 ,  Maria F Pazyra-Murphy  1  2 ,  Daina Avizonis  3 ,  Mariana de Sá Tavares Russo  3 ,  Sophia Tang  2 ,  Chiung-Ya Chen  4 ,  Yi-Ping Hsueh  4 ,  Johann S Bergholz  2  5  6 ,  Tao Jiang  2 ,  Jean J Zhao  2  5  6 ,  Jian Zhu  7 ,  Kwang Woo Ko  8 ,  Jeffrey Milbrandt  7  9 ,  Aaron DiAntonio  8  9 ,  Rosalind A Segal  1  2
Affiliations
  • 1. Department of Neurobiology, Harvard Medical School, Boston, MA.
  • 2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.
  • 3. Metabolomics Innovation Resource, Goodman Cancer Research Centre, McGill University, Montréal, Quebec, Canada.
  • 4. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, Republic of China.
  • 5. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA.
  • 6. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA.
  • 7. Department of Genetics, Washington University School of Medicine, St. Louis, MO.
  • 8. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO.
  • 9. Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO.
PMID: 34935867 DOI: 10.1083/jcb.202106080
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 paclitaxel-induced peripheral neuropathy (PIPN).

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