puc-header

Activation of Sarm1 Produces cADPR to Increase Intra-Axonal Calcium and Promote Axon Degeneration in CIPN

49 Pages Posted: 19 Apr 2021 Publication Status: Review Complete

See all articles by Yihang Li

Yihang Li

Harvard University - Dana-Farber Cancer Institute

Maria F. Pazyra-Murphy

Harvard University - Dana-Farber Cancer Institute

Daina Avizonis

McGill University - Metabolomics Core Facility

Mariana de Sa Tavares Russo

McGill University

sophia tang

Harvard University - Dana-Farber Cancer Institute

Johann S. Bergholz

Harvard University - Dana-Farber Cancer Institute

Tao Jiang

Harvard University - Department of Cancer Biology

Jean J. Zhao

Harvard University - Dana-Farber Cancer Institute

Jian Zhu

Washington University in St. Louis - Department of Genetics

Kwang Woo Ko

Washington University in St. Louis - Department of Genetics

Jeffrey Milbrandt

Washington University in St. Louis - Department of Genetics

Aaron DiAntonio

Washington University in St. Louis - Department of Genetics

Rosalind A. Segal

Harvard University - Dana-Farber Cancer Institute

More...

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.

Suggested Citation

Li, Yihang and Pazyra-Murphy, Maria F. and Avizonis, Daina and de Sa Tavares Russo, Mariana and tang, sophia and Bergholz, Johann S. and Jiang, Tao and Zhao, Jean J. and Zhu, Jian and Ko, Kwang Woo and Milbrandt, Jeffrey and DiAntonio, Aaron and Segal, Rosalind A., Activation of Sarm1 Produces cADPR to Increase Intra-Axonal Calcium and Promote Axon Degeneration in CIPN. Available at SSRN: https://ssrn.com/abstract=3830010 or http://dx.doi.org/10.2139/ssrn.3830010
This version of the paper has not been formally peer reviewed.

Yihang Li

Harvard University - Dana-Farber Cancer Institute

Maria F. Pazyra-Murphy

Harvard University - Dana-Farber Cancer Institute

450 Brookline Avenue
Boston, MA 02215
United States

Daina Avizonis

McGill University - Metabolomics Core Facility

Montreal, Quebec H3A 1A3
United States

Mariana De Sa Tavares Russo

McGill University

1001 Sherbrooke St. W
Montreal
Canada

Sophia Tang

Harvard University - Dana-Farber Cancer Institute

Johann S. Bergholz

Harvard University - Dana-Farber Cancer Institute

450 Brookline Avenue
Boston, MA 02215
United States

Tao Jiang

Harvard University - Department of Cancer Biology

450 Brookline Avenue
Boston, MA 02215
United States

Jean J. Zhao

Harvard University - Dana-Farber Cancer Institute

450 Brookline Avenue
Boston, MA 02215
United States

Jian Zhu

Washington University in St. Louis - Department of Genetics

4515 McKinley Ave
St. Louis, WA 63110
United States

Kwang Woo Ko

Washington University in St. Louis - Department of Genetics ( email )

4515 McKinley Ave
St. Louis, WA 63110
United States

Jeffrey Milbrandt

Washington University in St. Louis - Department of Genetics ( email )

4515 McKinley Ave
St. Louis, WA 63110
United States

Aaron DiAntonio

Washington University in St. Louis - Department of Genetics ( email )

4515 McKinley Ave
St. Louis, WA 63110
United States

Rosalind A. Segal (Contact Author)

Harvard University - Dana-Farber Cancer Institute

450 Brookline Avenue
Boston, MA 02215
United States

Click here to go to Cell.com

Paper statistics

Abstract Views
132
Downloads
6
PlumX Metrics