{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T19:19:51Z","timestamp":1793387991093,"version":"4.5.0"},"reference-count":76,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS079450"],"award-info":[{"award-number":["R01 NS079450"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R56 NS097813"],"award-info":[{"award-number":["R56 NS097813"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["NIH NIGMS 2P20GM103432"],"award-info":[{"award-number":["NIH NIGMS 2P20GM103432"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Huntington\u2019s disease (HD) is a neurodegenerative disorder caused by a dominant CAG-repeat expansion in the huntingtin gene. Microglial activation is a key feature of HD pathology, and is present before clinical disease onset. The kynurenine pathway (KP) of tryptophan degradation is activated in HD, and is thought to contribute to disease progression. Indoleamine-2,3-dioxygenase (IDO) catalyzes the first step in this pathway; this and other pathway enzymes reside with microglia. While HD brain microglia accumulate iron, the role of iron in promoting microglial activation and KP activity is unclear. Here we utilized the neonatal iron supplementation model to investigate the relationship between iron, microglial activation and neurodegeneration in adult HD mice. We show in the N171-82Q mouse model of HD microglial morphologic changes consistent with immune activation. Neonatal iron supplementation in these mice promoted neurodegeneration and resulted in additional microglial activation in adults as determined by increased soma volume and decreased process length. We further demonstrate that iron activates IDO, both in brain lysates and purified recombinant protein (EC\n                    <jats:sub>50<\/jats:sub>\n                    = 1.24 nM). Brain IDO activity is increased by HD. Neonatal iron supplementation further promoted IDO activity in cerebral cortex, altered KP metabolite profiles, and promoted HD neurodegeneration as measured by brain weights and striatal volumes. Our results demonstrate that dietary iron is an important activator of microglia and the KP pathway in this HD model, and that this occurs in part through a direct effect on IDO. The findings are relevant to understanding how iron promotes neurodegeneration in HD.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0250606","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T13:36:32Z","timestamp":1620999392000},"page":"e0250606","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":29,"title":["Iron activates microglia and directly stimulates indoleamine-2,3-dioxygenase activity in the N171-82Q mouse model of Huntington\u2019s disease"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8939-981X","authenticated-orcid":true,"given":"David W.","family":"Donley","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marley","family":"Realing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason P.","family":"Gigley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9311-5231","authenticated-orcid":true,"given":"Jonathan H.","family":"Fox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,5,14]]},"reference":[{"issue":"6","key":"pone.0250606.ref001","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes. 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