{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T17:09:49Z","timestamp":1787072989158,"version":"build-2736575974"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T00:00:00Z","timestamp":1669161600000},"content-version":"vor","delay-in-days":21,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Grant-in-Aid for Scientific Research","award":["JP16H01193"],"award-info":[{"award-number":["JP16H01193"]}]},{"name":"Grant-in-Aid for Scientific Research","award":["JP26111504"],"award-info":[{"award-number":["JP26111504"]}]},{"name":"Grant-in-Aid for Scientific Research","award":["JP21K07826"],"award-info":[{"award-number":["JP21K07826"]}]},{"name":"Grant-in-Aid for JSPS Fellows","award":["JP21J15642"],"award-info":[{"award-number":["JP21J15642"]}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science, and Technology","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"name":"JMU Graduate Student Research Award"},{"DOI":"10.13039\/501100005744","name":"Foundation for Pediatric Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005744","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Terumo Life Science Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Static encephalopathy of childhood with neurodegeneration in adulthood\/\u03b2-propeller protein-associated neurodegeneration is a neurodegenerative disorder with brain iron accumulation caused by the variants of WDR45, a core autophagy-related gene that encodes WD repeat domain phosphoinositide interacting protein 4. However, the pathophysiology of the disease, particularly the function of WDR45\/WD repeat domain phosphoinositide interacting protein 4 in iron metabolism, is largely unknown. As no other variants of core autophagy-related genes show abnormalities in iron metabolism, the relation between autophagy and iron metabolism remains to be elucidated. Since iron deposition in the brain is the hallmark of static encephalopathy of childhood with neurodegeneration in adulthood\/\u03b2-propeller protein-associated neurodegeneration, iron chelation therapy has been attempted, but it was found to worsen the symptoms; thus, the establishment of a curative treatment is essential. Here, we evaluated autophagy and iron metabolism in patient-derived cells. The expression of ferritin and ferric iron increased and that of ferrous iron decreased in the patient cells with WDR45 variants. In addition, the expression of nuclear receptor coactivator 4 was markedly reduced in patient-derived cells. Furthermore, divalent metal transporter 1, which takes in ferrous iron, was upregulated, while ferroportin, which exports ferrous iron, was downregulated in patient-derived cells. The transfer of WDR45 via an adeno-associated virus vector restored WD repeat domain phosphoinositide interacting protein 4 and nuclear receptor coactivator 4 expression, reduced ferritin levels, and improved other phenotypes observed in patient-derived cells. As nuclear receptor coactivator 4 mediates the ferritin-specific autophagy, i.e. ferritinophagy, its deficiency impaired ferritinophagy, leading to the accumulation of ferric iron-containing ferritin and insufficiency of ferrous iron. Because ferrous iron is required for various essential biochemical reactions, the changes in divalent metal transporter 1 and ferroportin levels may indicate a compensatory response for maintaining the intracellular levels of ferrous iron. Our study revealed that the pathophysiology of static encephalopathy of childhood with neurodegeneration in adulthood\/\u03b2-propeller protein-associated neurodegeneration involves ferrous iron insufficiency via impaired ferritinophagy through nuclear receptor coactivator 4 expression reduction. Our findings could aid in developing a treatment strategy involving WDR45 manipulation, which may have clinical applications.<\/jats:p>","DOI":"10.1093\/braincomms\/fcac304","type":"journal-article","created":{"date-parts":[[2022,11,18]],"date-time":"2022-11-18T21:40:47Z","timestamp":1668807647000},"source":"Crossref","is-referenced-by-count":22,"title":["<i>WDR45<\/i> variants cause ferrous iron loss due to impaired ferritinophagy associated with nuclear receptor coactivator 4 and WD repeat domain phosphoinositide interacting protein 4 reduction"],"prefix":"10.1093","volume":"4","author":[{"given":"Kiwako","family":"Tsukida","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University , Tochigi 329-0498 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin-ichi","family":"Muramatsu","sequence":"additional","affiliation":[{"name":"Division of Neurological Gene Therapy, Jichi Medical University , Tochigi 329-0498 , Japan"},{"name":"Center for Gene & Cell Therapy, The Institute of Medical Science, The University of Tokyo , Tokyo 108-8639 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Osaka","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University , Tochigi 329-0498 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3961-9922","authenticated-orcid":false,"given":"Takanori","family":"Yamagata","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University , Tochigi 329-0498 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9256-5591","authenticated-orcid":false,"given":"Kazuhiro","family":"Muramatsu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Jichi Medical University , Tochigi 329-0498 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,11,23]]},"reference":[{"key":"2022121612150132000_fcac304-B1","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1016\/j.ajhg.2012.10.019","article-title":"Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA","volume":"91","author":"Haack","year":"2012","journal-title":"Am J Hum Genet"},{"key":"2022121612150132000_fcac304-B2","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1093\/brain\/awt095","article-title":"Beta-propeller protein-associated neurodegeneration: A new X-linked dominant disorder with brain iron accumulation","volume":"136","author":"Hayflick","year":"2013","journal-title":"Brain"},{"key":"2022121612150132000_fcac304-B3","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3174\/ajnr.A2677","article-title":"Neuroimaging features of neurodegeneration with brain iron accumulation","volume":"33","author":"Kruer","year":"2012","journal-title":"Am J Neuroradiol"},{"key":"2022121612150132000_fcac304-B4","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/ng.2562","article-title":"De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood","volume":"45","author":"Saitsu","year":"2013","journal-title":"Nat Genet"},{"key":"2022121612150132000_fcac304-B5","volume-title":"Genereviews\u00ae","author":"Gregory","year":"1993-2022"},{"key":"2022121612150132000_fcac304-B6","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cell.2018.09.048","article-title":"Biological functions of autophagy genes: A disease perspective","volume":"176","author":"Levine","year":"2019","journal-title":"Cell"},{"key":"2022121612150132000_fcac304-B7","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.cell.2011.10.026","article-title":"Autophagy: Renovation of cells and tissues","volume":"147","author":"Mizushima","year":"2011","journal-title":"Cell"},{"key":"2022121612150132000_fcac304-B8","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/s41556-018-0092-5","article-title":"A brief history of autophagy from cell biology to physiology and disease","volume":"20","author":"Mizushima","year":"2018","journal-title":"Nat Cell Biol"},{"key":"2022121612150132000_fcac304-B9","doi-asserted-by":"crossref","first-page":"E9792","DOI":"10.1073\/pnas.1811874115","article-title":"Insights into autophagosome biogenesis from structural and biochemical analyses of the ATG2A\u2013WIPI4 complex","volume":"115","author":"Chowdhury","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022121612150132000_fcac304-B10","doi-asserted-by":"crossref","first-page":"10540","DOI":"10.1073\/pnas.1814759115","article-title":"Membrane tethering by the autophagy ATG2A-WIPI4 complex","volume":"115","author":"Graef","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022121612150132000_fcac304-B11","doi-asserted-by":"crossref","first-page":"e45777","DOI":"10.7554\/eLife.45777","article-title":"The autophagic membrane tether ATG2A transfers lipids between membranes","volume":"8","author":"Maeda","year":"2019","journal-title":"Elife"},{"key":"2022121612150132000_fcac304-B12","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/gtc.12733","article-title":"Human ATG2B possesses a lipid transfer activity which is accelerated by negatively charged lipids and WIPI4","volume":"25","author":"Osawa","year":"2020","journal-title":"Genes Cells"},{"key":"2022121612150132000_fcac304-B13","doi-asserted-by":"crossref","DOI":"10.1177\/2515256418819936","article-title":"The rod-shaped ATG2A-WIPI4 complex tethers membranes in vitro","volume":"1","author":"Otomo","year":"2018","journal-title":"Contact"},{"key":"2022121612150132000_fcac304-B14","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1146\/annurev.physiol.69.031905.164337","article-title":"Iron homeostasis","volume":"69","author":"Andrews","year":"2007","journal-title":"Annu Rev Physiol"},{"key":"2022121612150132000_fcac304-B15","first-page":"324","article-title":"The hydroxyl radical: From chemistry to human disease","volume":"44","author":"Lubec","year":"1996","journal-title":"J Investig Med"},{"key":"2022121612150132000_fcac304-B16","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.taap.2004.06.021","article-title":"Iron metabolism and toxicity","volume":"202","author":"Papanikolaou","year":"2005","journal-title":"Toxicol Appl Pharmacol"},{"key":"2022121612150132000_fcac304-B17","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1016\/S1474-4422(14)70117-6","article-title":"The role of iron in brain ageing and neurodegenerative disorders","volume":"13","author":"Ward","year":"2014","journal-title":"Lancet Neurol"},{"key":"2022121612150132000_fcac304-B18","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.bbagen.2008.09.004","article-title":"Ferritins: A family of molecules for iron storage, antioxidation and more","volume":"1790","author":"Arosio","year":"2009","journal-title":"Biochim Biophys Acta"},{"key":"2022121612150132000_fcac304-B19","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1182\/blood.V99.10.3505","article-title":"Regulation of ferritin genes and protein","volume":"99","author":"Torti","year":"2002","journal-title":"Blood"},{"key":"2022121612150132000_fcac304-B20","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nature13148","article-title":"Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy","volume":"509","author":"Mancias","year":"2014","journal-title":"Nature"},{"key":"2022121612150132000_fcac304-B21","doi-asserted-by":"crossref","first-page":"238","DOI":"10.3389\/fnins.2019.00238","article-title":"NCOA4-mediated ferritinophagy: A potential link to neurodegeneration","volume":"13","author":"Quiles Del Rey","year":"2019","journal-title":"Front Neurosci"},{"key":"2022121612150132000_fcac304-B22","doi-asserted-by":"crossref","first-page":"18","DOI":"10.3389\/fgene.2017.00018","article-title":"Ferrous iron up-regulation in fibroblasts of patients with beta propeller protein-associated neurodegeneration (BPAN)","volume":"8","author":"Ingrassia","year":"2017","journal-title":"Front Genet"},{"key":"2022121612150132000_fcac304-B23","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1093\/brain\/awy230","article-title":"Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells","volume":"141","author":"Seibler","year":"2018","journal-title":"Brain"},{"key":"2022121612150132000_fcac304-B24","doi-asserted-by":"crossref","first-page":"645831","DOI":"10.3389\/fmolb.2021.645831","article-title":"WDR45 Mutation impairs the autophagic degradation of transferrin receptor and promotes ferroptosis","volume":"8","author":"Xiong","year":"2021","journal-title":"Front Mol Biosci"},{"key":"2022121612150132000_fcac304-B25","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.neurad.2020.04.002","article-title":"Serial MRI alterations of pediatric patients with beta-propeller protein associated neurodegeneration (BPAN)","volume":"48","author":"Kimura","year":"2021","journal-title":"J Neuroradiol"},{"key":"2022121612150132000_fcac304-B26","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/j.molcel.2016.09.037","article-title":"An autophagic flux probe that releases an internal control","volume":"64","author":"Kaizuka","year":"2016","journal-title":"Mol Cell"},{"key":"2022121612150132000_fcac304-B27","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1016\/j.tibs.2020.07.006","article-title":"Autophagy assays for biological discovery and therapeutic development","volume":"45","author":"Mizushima","year":"2020","journal-title":"Trends Biochem Sci"},{"key":"2022121612150132000_fcac304-B28","doi-asserted-by":"crossref","first-page":"6381","DOI":"10.1128\/JVI.78.12.6381-6388.2004","article-title":"Clades of adeno-associated viruses are widely disseminated in human tissues","volume":"78","author":"Gao","year":"2004","journal-title":"J Virol"},{"key":"2022121612150132000_fcac304-B29","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/mt.2010.234","article-title":"Novel properties of tyrosine-mutant AAV2 vectors in the mouse retina","volume":"19","author":"Petrs-Silva","year":"2011","journal-title":"Mol Ther"},{"key":"2022121612150132000_fcac304-B30","doi-asserted-by":"crossref","first-page":"974819","DOI":"10.1155\/2013\/974819","article-title":"Systemic delivery of tyrosine-mutant AAV vectors results in robust transduction of neurons in adult mice","volume":"2013","author":"Iida","year":"2013","journal-title":"Biomed Res Int"},{"key":"2022121612150132000_fcac304-B31","doi-asserted-by":"crossref","first-page":"16344","DOI":"10.1038\/s41598-019-52735-z","article-title":"Rotigotine suppresses sleep-related muscle activity augmented by injection of dialysis patients\u2019 sera in a mouse model of restless legs syndrome","volume":"9","author":"Muramatsu","year":"2019","journal-title":"Sci Rep"},{"key":"2022121612150132000_fcac304-B32","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/ncb3053","article-title":"Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo","volume":"16","author":"Dowdle","year":"2014","journal-title":"Nat Cell Biol"},{"key":"2022121612150132000_fcac304-B33","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.3390\/antiox9101020","article-title":"Mitochondrial dysfunction, oxidative stress and neuroinflammation in Neurodegeneration with Brain Iron Accumulation (NBIA)","volume":"9","author":"Hinarejos","year":"2020","journal-title":"Antioxidants (Basel)"},{"key":"2022121612150132000_fcac304-B34","doi-asserted-by":"crossref","first-page":"3866","DOI":"10.1002\/ajmg.a.62442","article-title":"Autophagic defects observed in fibroblasts from a patient with \u03b2-propeller protein-associated neurodegeneration","volume":"185","author":"Lee","year":"2021","journal-title":"Am J Med Genet A"},{"key":"2022121612150132000_fcac304-B35","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1080\/15548627.2015.1047127","article-title":"The autophagy gene Wdr45\/Wipi4 regulates learning and memory function and axonal homeostasis","volume":"11","author":"Zhao","year":"2015","journal-title":"Autophagy"},{"key":"2022121612150132000_fcac304-B36","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1097\/MCO.0b013e32831ba07c","article-title":"Role of iron in neurotoxicity: A cause for concern in the elderly?","volume":"12","author":"Stankiewicz","year":"2009","journal-title":"Curr Opin Clin Nutr Metab Care"},{"key":"2022121612150132000_fcac304-B37","doi-asserted-by":"crossref","first-page":"1634","DOI":"10.1111\/j.1471-4159.2006.03907.x","article-title":"Oxidative stress and neurodegeneration: Where are we now?","volume":"97","author":"Halliwell","year":"2006","journal-title":"J Neurochem"},{"key":"2022121612150132000_fcac304-B38","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nrn3453","article-title":"Iron metabolism in the CNS: Implications for neurodegenerative diseases","volume":"14","author":"Rouault","year":"2013","journal-title":"Nat Rev Neurosci"},{"key":"2022121612150132000_fcac304-B39","doi-asserted-by":"crossref","first-page":"157","DOI":"10.4161\/auto.6.1.10587","article-title":"Autophagy, ferritin and iron chelation","volume":"6","author":"De Domenico","year":"2010","journal-title":"Autophagy"},{"key":"2022121612150132000_fcac304-B40","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.celrep.2015.12.065","article-title":"NCOA4 deficiency impairs systemic iron homeostasis","volume":"14","author":"Bellelli","year":"2016","journal-title":"Cell Rep"},{"key":"2022121612150132000_fcac304-B41","doi-asserted-by":"crossref","first-page":"3908","DOI":"10.1080\/15548627.2021.1899669","article-title":"WDR45, one gene associated with multiple neurodevelopmental disorders","volume":"17","author":"Cong","year":"2021","journal-title":"Autophagy"},{"key":"2022121612150132000_fcac304-B42","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1080\/17474086.2016.1268047","article-title":"Mitochondria and iron: Current questions","volume":"10","author":"Paul","year":"2017","journal-title":"Expert Rev Hematol"},{"key":"2022121612150132000_fcac304-B43","doi-asserted-by":"crossref","first-page":"e00010-19","DOI":"10.1128\/MCB.00010-19","article-title":"Iron supply via NCOA4-mediated ferritin degradation maintains mitochondrial functions","volume":"39","author":"Fujimaki","year":"2019","journal-title":"Mol Cell Biol"},{"key":"2022121612150132000_fcac304-B44","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1080\/15548627.2019.1630224","article-title":"WDR45 contributes to neurodegeneration through regulation of ER homeostasis and neuronal death","volume":"16","author":"Wan","year":"2020","journal-title":"Autophagy"},{"key":"2022121612150132000_fcac304-B45","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1080\/15548627.2019.1632621","article-title":"Wdr45b in maintaining neural autophagy and cognitive function","volume":"16","author":"Ji","year":"2020","journal-title":"Autophagy"},{"key":"2022121612150132000_fcac304-B46","doi-asserted-by":"crossref","first-page":"180","DOI":"10.3389\/fnins.2019.00180","article-title":"Iron in neurodegeneration \u2013 cause or consequence?","volume":"13","author":"Ndayisaba","year":"2019","journal-title":"Front Neurosci"},{"key":"2022121612150132000_fcac304-B47","doi-asserted-by":"crossref","first-page":"385","DOI":"10.3389\/fneur.2017.00385","article-title":"Patient affected by beta-propeller protein-associated neurodegeneration: A therapeutic attempt with iron chelation therapy","volume":"8","author":"Fonderico","year":"2017","journal-title":"Front Neurol"},{"key":"2022121612150132000_fcac304-B48","doi-asserted-by":"crossref","first-page":"89","DOI":"10.14802\/jmd.17082","article-title":"A patient with beta-propeller protein-associated neurodegeneration: Treatment with iron chelation therapy","volume":"11","author":"Lim","year":"2018","journal-title":"J Mov Disord"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcac304\/47162334\/fcac304.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/4\/6\/fcac304\/47998331\/fcac304.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/braincomms\/article-pdf\/4\/6\/fcac304\/47998331\/fcac304.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T13:12:53Z","timestamp":1671196373000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcac304\/6835456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,2]]},"references-count":48,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,11,2]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcac304","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,1]]},"published":{"date-parts":[[2022,11,2]]},"article-number":"fcac304"}}