2. Academic Validation
  3. Sarm1 activation produces cADPR to increase intra-axonal Ca++ and promote axon degeneration in PIPN

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

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).

Figures
Products