{"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":1789641311900,"version":"4.0.0"},"reference-count":28,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,4,28]],"date-time":"2024-04-28T00:00:00Z","timestamp":1714262400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology Appl Neurobio"],"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>\n                      Leigh syndrome (LS), the most common paediatric presentation of genetic mitochondrial dysfunction, is a multi\u2010system disorder characterised by severe neurologic and metabolic abnormalities. Symmetric, bilateral, progressive necrotizing lesions in the brainstem are defining features of the disease. Patients are often symptom free in early life but typically develop symptoms by about 2\u2009years of age. The mechanisms underlying disease onset and progression in LS remain obscure. Recent studies have shown that the immune system causally drives disease in the\n                      <jats:italic>Ndufs4<\/jats:italic>\n                      (\u2212\/\u2212) mouse model of LS: treatment of\n                      <jats:italic>Ndufs4<\/jats:italic>\n                      (\u2212\/\u2212) mice with the macrophage\u2010depleting Csf1r inhibitor pexidartinib prevents disease. While the precise mechanisms leading to immune activation and immune factors involved in disease progression have not yet been determined, interferon\u2010gamma (IFN\u03b3) and interferon gamma\u2010induced protein 10 (IP10) were found to be significantly elevated in\n                      <jats:italic>Ndufs4<\/jats:italic>\n                      (\u2212\/\u2212) brainstem, implicating these factors in disease. Here, we aimed to explore the role of IFN\u03b3 and IP10 in LS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To establish the role of IFN\u03b3 and IP10 in LS, we generated IFN\u03b3 and IP10 deficient\n                      <jats:italic>Ndufs4<\/jats:italic>\n                      (\u2212\/\u2212)\/\n                      <jats:italic>Ifng<\/jats:italic>\n                      (\u2212\/\u2212) and\n                      <jats:italic>Ndufs4<\/jats:italic>\n                      (\u2212\/\u2212)\/\n                      <jats:italic>IP10<\/jats:italic>\n                      (\u2212\/\u2212) double knockout animals, as well as IFN\u03b3 and IP10 heterozygous,\n                      <jats:italic>Ndufs4<\/jats:italic>\n                      (\u2212\/\u2212)\/\n                      <jats:italic>Ifng<\/jats:italic>\n                      (+\/\u2212) and\n                      <jats:italic>Ndufs4<\/jats:italic>\n                      (\u2212\/\u2212)\/\n                      <jats:italic>IP10<\/jats:italic>\n                      (+\/\u2212), animals. We monitored disease onset and progression to define the impact of heterozygous or homozygous loss of IFN\u03b3 and IP10 in LS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Loss of IP10 does not significantly impact the onset or progression of disease in the\n                      <jats:italic>Ndufs4<\/jats:italic>\n                      (\u2212\/\u2212) model. IFN\u03b3 loss significantly extends survival and delays disease progression in a gene dosage\u2010dependent manner, though the benefits are modest compared to Csf1r inhibition.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>IFN\u03b3 contributes to disease onset and progression in LS. Our findings suggest that IFN\u03b3 targeting therapies may provide some benefits in genetic mitochondrial disease, but targeting IFN\u03b3 alone would likely yield only modest benefits in LS.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nan.12977","type":"journal-article","created":{"date-parts":[[2024,4,29]],"date-time":"2024-04-29T02:49:35Z","timestamp":1714358975000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Interferon\u2010gamma contributes to disease progression in the\n                    <i>Ndufs4<\/i>\n                    (\u2212\/\u2212) model of Leigh syndrome"],"prefix":"10.1111","volume":"50","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":"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":"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":"Ryan","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":"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":"Ernst\u2010Bernhard","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":"Kino","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute  Seattle Washington 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