{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T10:35:11Z","timestamp":1789641311884,"version":"4.0.0"},"reference-count":30,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T00:00:00Z","timestamp":1691452800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100003138","name":"Mitochondrial Research Guild","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003138","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["R01\u2010133865"],"award-info":[{"award-number":["R01\u2010133865"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health and Care Research","doi-asserted-by":"publisher","award":["R01NS119426"],"award-info":[{"award-number":["R01NS119426"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Brain Pathology"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi\u2010system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high\u2010dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the <jats:italic>Ndufs4<\/jats:italic>(\u2212\/\u2212) mouse model of LS. While the dose\u2013response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony\u2010stimulating Factor 1 receptor (CSF1R) macrophage super\u2010enhancer FIRE (<jats:italic>Csf1r<\/jats:italic>\u0394FIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the <jats:italic>Csf1r<\/jats:italic>\u0394FIRE allele ablates microglia in both control and <jats:italic>Ndufs4<\/jats:italic>(\u2212\/\u2212) animals, but onset of CNS lesions and sequalae in the <jats:italic>Ndufs4<\/jats:italic>(\u2212\/\u2212), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the <jats:italic>Ndufs4<\/jats:italic>(\u2212\/\u2212) model.<\/jats:p>","DOI":"10.1111\/bpa.13192","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T18:54:46Z","timestamp":1691520886000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Peripheral macrophages drive <scp>CNS<\/scp> disease in the <i>Ndufs4<\/i>(\u2212\/\u2212) model of Leigh syndrome"],"prefix":"10.1111","volume":"33","author":[{"given":"Allison R.","family":"Hanaford","sequence":"first","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asheema","family":"Khanna","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer Research Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian","family":"Truong","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina","family":"James","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihan","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mulholland","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Kayser","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan W.","family":"Liao","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Sedensky","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"},{"name":"Department of Anesthesiology and Pain Medicine University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phil","family":"Morgan","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"},{"name":"Department of Anesthesiology and Pain Medicine University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan Andrew","family":"Baertsch","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"},{"name":"Department of Pediatrics University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vandana","family":"Kalia","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer Research Seattle Children's Research Institute  Seattle Washington USA"},{"name":"Department of Pediatrics University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surojit","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Ben Towne Center for Childhood Cancer Research Seattle Children's Research Institute  Seattle Washington USA"},{"name":"Department of Pediatrics University of Washington School of Medicine  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1942-3674","authenticated-orcid":false,"given":"Simon C.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington USA"},{"name":"Department of Anesthesiology and Pain Medicine University of Washington  Seattle Washington USA"},{"name":"Department of Laboratory Medicine and Pathology University of Washington  Seattle Washington USA"},{"name":"Department of Neurology University of Washington  Seattle Washington USA"},{"name":"Department of Applied Sciences, Translational Bioscience Northumbria University  Newcastle Upon Tyne UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,8]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0000000000000195"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24551"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.00267"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2008.02.004"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab426"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.156522"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a021857"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2020.00893"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2019.04.011"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.14.3.216"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1006214107"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0169-328x(98)00040-0"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.122.040302"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11053-8"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.70.5.812"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0026317"},{"key":"e_1_2_11_18_1","unstructured":"RojoR.Role 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