Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program

Stefanie Geisler, Ryan A. Doan, Galen C. Cheng, Aysel Cetinkaya-Fisgin, Shay X. Huang, Ahmet Hoke, Jeffrey Milbrandt, Aaron DiAntonio

Research output: Contribution to journalArticle

Abstract

Chemotherapy-induced peripheral neuropathy is one of the most prevalent dose-limiting toxicities of anticancer therapy. Development of effective therapies to prevent chemotherapy-induced neuropathies could be enabled by a mechanistic understanding of axonal breakdown following exposure to neuropathy-causing agents. Here, we reveal the molecular mechanisms underlying axon degeneration induced by 2 widely used chemotherapeutic agents with distinct mechanisms of action: vincristine and bortezomib. We showed previously that genetic deletion of SARM1 blocks vincristine-induced neuropathy and demonstrate here that it also prevents axon destruction following administration of bortezomib in vitro and in vivo. Using cultured neurons, we found that vincristine and bortezomib converge on a core axon degeneration program consisting of nicotinamide mononucleotide NMNAT2, SARM1, and loss of NAD+ but engage different upstream mechanisms that closely resemble Wallerian degeneration after vincristine and apoptosis after bortezomib. We could inhibit the final common axon destruction pathway by preserving axonal NAD+ levels or expressing a candidate gene therapeutic that inhibits SARM1 in vitro. We suggest that these approaches may lead to therapies for vincristine- and bortezomib-induced neuropathies and possibly other forms of peripheral neuropathy.

Original languageEnglish (US)
Article numbere129920
JournalJCI Insight
Volume4
Issue number17
DOIs
StatePublished - Sep 5 2019

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Vincristine
Axons
Peripheral Nervous System Diseases
NAD
Nicotinamide Mononucleotide
Wallerian Degeneration
Drug Therapy
Therapeutics
Bortezomib
Apoptosis
Neurons
Genes
In Vitro Techniques

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Geisler, S., Doan, R. A., Cheng, G. C., Cetinkaya-Fisgin, A., Huang, S. X., Hoke, A., ... DiAntonio, A. (2019). Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program. JCI Insight, 4(17), [e129920]. https://doi.org/10.1172/jci.insight.129920

Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program. / Geisler, Stefanie; Doan, Ryan A.; Cheng, Galen C.; Cetinkaya-Fisgin, Aysel; Huang, Shay X.; Hoke, Ahmet; Milbrandt, Jeffrey; DiAntonio, Aaron.

In: JCI Insight, Vol. 4, No. 17, e129920, 05.09.2019.

Research output: Contribution to journalArticle

Geisler, S, Doan, RA, Cheng, GC, Cetinkaya-Fisgin, A, Huang, SX, Hoke, A, Milbrandt, J & DiAntonio, A 2019, 'Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program', JCI Insight, vol. 4, no. 17, e129920. https://doi.org/10.1172/jci.insight.129920
Geisler, Stefanie ; Doan, Ryan A. ; Cheng, Galen C. ; Cetinkaya-Fisgin, Aysel ; Huang, Shay X. ; Hoke, Ahmet ; Milbrandt, Jeffrey ; DiAntonio, Aaron. / Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program. In: JCI Insight. 2019 ; Vol. 4, No. 17.
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