{"doi":"10.1242/dmm.049358","title":"Bortezomib-induced neurotoxicity in human neurons is the consequence of nicotinamide adenine dinucleotide depletion","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.","journal":"Disease Models & Mechanisms","year":2022,"id":258099,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":909729,"name":"Keungjung Heo","orcid":null,"position":1,"is_corresponding":false},{"id":307213,"name":"Veselina Petrova","orcid":"0000-0002-5593-0198","position":2,"is_corresponding":false},{"id":498262,"name":"Tammy Szu‐Yu Ho","orcid":null,"position":3,"is_corresponding":false},{"id":641762,"name":"Xuan Huang","orcid":"0000-0002-1116-0865","position":4,"is_corresponding":false},{"id":909730,"name":"Crystal Hermawan","orcid":null,"position":5,"is_corresponding":false},{"id":909731,"name":"Ruth D. Kagan","orcid":null,"position":6,"is_corresponding":false},{"id":625107,"name":"Tao Deng","orcid":"0000-0002-8303-0891","position":7,"is_corresponding":false},{"id":560507,"name":"Ilyas Singeç","orcid":"0000-0003-3941-1838","position":8,"is_corresponding":false},{"id":909134,"name":"Long Chen","orcid":"0000-0001-8677-803X","position":9,"is_corresponding":false},{"id":909732,"name":"Lee B. Barret","orcid":null,"position":10,"is_corresponding":false},{"id":262675,"name":"Clifford J. Woolf","orcid":"0000-0002-6636-3897","position":11,"is_corresponding":false},{"id":694953,"name":"Andrew Snavely","orcid":"0000-0001-9185-5765","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T00:25:38.634785Z","pmid":"36398590","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}