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© 2022. This work is licensed under https://creativecommons.org/licenses/by/4.0 (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

The proteosome inhibitor bortezomib has revolutionized the treatment of multiple hematologic malignancies, but in many cases, its efficacy is limited by a dose-dependent peripheral neuropathy. We show that human induced pluripotent stem cell (hiPSC)-derived motor neurons and sensory neurons provide a model system for the study of bortezomib-induced peripheral neuropathy, with promising implications for furthering the mechanistic understanding of and developing treatments for preventing axonal damage. Human neurons in tissue culture displayed distal-to-proximal neurite degeneration when exposed to bortezomib. This process coincided with disruptions in mitochondrial function and energy homeostasis, similar to those described in rodent models of bortezomib-induced neuropathy. Moreover, although the degenerative process was unaffected by inhibition of caspases, it was completely blocked by exogenous nicotinamide adenine dinucleotide (NAD+), a mediator of the SARM1-dependent axon degeneration pathway. We demonstrate that bortezomib-induced neurotoxicity in relevant human neurons proceeds through mitochondrial dysfunction and NAD+ depletion-mediated axon degeneration, raising the possibility that targeting these changes might provide effective therapeutics for the prevention of bortezomib-induced neuropathy and that modeling chemotherapy-induced neuropathy in human neurons has utility.

Details

Title
Bortezomib-induced neurotoxicity in human neurons is the consequence of nicotinamide adenine dinucleotide depletion
Author
Snavely, Andrew R  VIAFID ORCID Logo  ; Heo, Keungjung; Petrova, Veselina; Tammy Szu-Yu Ho; Huang, Xuan  VIAFID ORCID Logo  ; Hermawan, Crystal; Kagan, Ruth; Deng, Tao; Ilyas Singeç; Long, Chen; Barret, Lee B; Woolf, Clifford J  VIAFID ORCID Logo 
Section
RESEARCH ARTICLES
Publication year
2022
Publication date
2022
Publisher
The Company of Biologists Ltd
ISSN
17548403
e-ISSN
17548411
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2760599217
Copyright
© 2022. This work is licensed under https://creativecommons.org/licenses/by/4.0 (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.