{"doi":"10.1172/jci159800","title":"Macrophage depletion blocks congenital SARM1-dependent neuropathy","abstract":"Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified 2 rare NMNAT2 missense variants in 2 brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions V98M and R232Q, which reduced NMNAT2 NAD+-synthetase activity. We generated a mouse model to mirror the human syndrome and found that Nmnat2V98M/R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed neuropathic phenotypes in Nmnat2V98M/R232Q mice, identifying a SARM1-dependent neuroimmune mechanism as a key driver of disease pathogenesis. These findings demonstrate that SARM1 induced inflammatory neuropathy and highlight the potential of immune therapy as a treatment for this rare syndrome and other neurodegenerative conditions associated with NMNAT2 loss and SARM1 activation.","journal":"Journal of Clinical Investigation","year":2022,"id":243200,"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":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"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":415892,"name":"Amy Strickland","orcid":"0000-0002-5809-8464","position":1,"is_corresponding":false},{"id":250748,"name":"Sabrina W. Yum","orcid":"0000-0002-5243-5546","position":2,"is_corresponding":false},{"id":30983,"name":"Aldrin Kay‐Yuen Yim","orcid":"0000-0001-9562-2328","position":3,"is_corresponding":false},{"id":640716,"name":"Jian Zhu","orcid":"0000-0001-6679-8498","position":4,"is_corresponding":false},{"id":252038,"name":"Peter L. Wang","orcid":"0000-0001-9651-3860","position":5,"is_corresponding":false},{"id":389104,"name":"Yurie Yamada","orcid":"0000-0002-0515-1807","position":6,"is_corresponding":false},{"id":254717,"name":"Robert E. Schmidt","orcid":"0000-0002-8334-5893","position":7,"is_corresponding":false},{"id":267988,"name":"Yo Sasaki","orcid":"0000-0003-0024-0031","position":8,"is_corresponding":false},{"id":683165,"name":"A. Joseph Bloom","orcid":"0000-0002-6731-5539","position":9,"is_corresponding":false},{"id":256133,"name":"Aaron DiAntonio","orcid":"0000-0002-7262-0968","position":10,"is_corresponding":false},{"id":240472,"name":"Jeffrey Milbrandt","orcid":"0000-0002-5477-7689","position":11,"is_corresponding":false},{"id":683163,"name":"Caitlin B. Dingwall","orcid":"0000-0002-2623-0547","position":0,"is_corresponding":true}],"reference_count":99,"raw_metadata":null,"created_at":"2026-07-19T00:23:16.032700Z","pmid":"36287209","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":[]}