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 mechanistic understanding and developing treatments for preventing axonal damage. Human neurons in tissue culture display distal-to-proximal neurite degeneration when exposed to bortezomib. This process coincides with disruptions in mitochondrial function and energy homeostasis similar to those described in rodent models of bortezomib-induced neuropathy. Moreover, while the degenerative process is unaffected by inhibition of caspases, it is 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 the NAD+ depletion mediated axon degeneration, raising the possibility that targeting these changes may provide effective therapeutics for the prevention of bortezomib-induced neuropathy and that modeling chemotherapy-induced neuropathy in human neurons has utility.
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