{"doi":"10.1101/2021.04.15.440024","title":"Activation of Sarm1 produces cADPR to increase intra-axonal calcium and promote axon degeneration in CIPN","abstract":"SUMMARY 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. HIGHLIGHTS Paclitaxel induces intra-axonal calcium flux Sarm1-dependent cADPR production promotes axonal calcium elevation and degeneration Antagonizing cADPR signaling pathway protects against paclitaxel-induced peripheral neuropathy in vitro and in vivo","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":216512,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9524,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":292185,"name":"Maria F. Pazyra‐Murphy","orcid":"0009-0005-1076-4551","position":1,"is_corresponding":false},{"id":316421,"name":"Daina Avizonis","orcid":"0000-0002-3843-255X","position":2,"is_corresponding":false},{"id":640712,"name":"Mariana De Sa Tavares Russo","orcid":"0000-0002-6626-5760","position":3,"is_corresponding":false},{"id":640713,"name":"Sophia Tang","orcid":"0000-0002-9209-3763","position":4,"is_corresponding":false},{"id":323165,"name":"Johann S. Bergholz","orcid":"0000-0003-4609-8448","position":5,"is_corresponding":false},{"id":640715,"name":"Tao Jiang","orcid":"0000-0002-6008-9049","position":6,"is_corresponding":false},{"id":236062,"name":"Jean J. Zhao","orcid":"0000-0002-4561-5688","position":7,"is_corresponding":false},{"id":640716,"name":"Jian Zhu","orcid":"0000-0001-6679-8498","position":8,"is_corresponding":false},{"id":262162,"name":"Kwang Woo Ko","orcid":"0000-0003-3813-8913","position":9,"is_corresponding":false},{"id":240472,"name":"Jeffrey Milbrandt","orcid":"0000-0002-5477-7689","position":10,"is_corresponding":false},{"id":256133,"name":"Aaron DiAntonio","orcid":"0000-0002-7262-0968","position":11,"is_corresponding":false},{"id":1406,"name":"Rosalind A. Segal","orcid":"0000-0001-9850-8432","position":12,"is_corresponding":false},{"id":292186,"name":"Yihang Li","orcid":"0000-0002-4824-2274","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-18T23:53:11.245932Z","pmid":null,"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":[]}