title: Brain iron accumulation affects myelin-related molecular systems implicated in a rare neurogenetic disease family with neuropsychiatric features.
abstract: The 'neurodegeneration with brain iron accumulation' (NBIA) disease family entails movement or cognitive impairment, often with psychiatric features. To understand how iron loading affects the brain, we studied mice with disruption of two iron regulatory genes, hemochromatosis (Hfe) and transferrin receptor 2 (Tfr2). Inductively coupled plasma atomic emission spectroscopy demonstrated increased iron in the Hfe-/-× Tfr2mutbrain (P=0.002, n ≥5/group), primarily localized by Perls' staining to myelinated structures. Western immunoblotting showed increases of the iron storage protein ferritin light polypeptide and microarray and real-time reverse transcription-PCR revealed decreased transcript levels (P<0.04, n ≥5/group) for five other NBIA genes, phospholipase A2 group VI, fatty acid 2-hydroxylase, ceruloplasmin, chromosome 19 open reading frame 12 and ATPase type 13A2. Apart from the ferroxidase ceruloplasmin, all are involved in myelin homeostasis; 16 other myelin-related genes also showed reduced expression (P<0.05), although gross myelin structure and integrity appear unaffected (P>0.05). Overlap (P<0.0001) of differentially expressed genes in Hfe-/-× Tfr2mutbrain with human gene co-expression networks suggests iron loading influences expression of NBIA-related and myelin-related genes co-expressed in normal human basal ganglia. There was overlap (P<0.0001) of genes differentially expressed in Hfe-/-× Tfr2mutbrain and post-mortem NBIA basal ganglia. Hfe-/-× Tfr2mutmice were hyperactive (P<0.0112) without apparent cognitive impairment by IntelliCage testing (P>0.05). These results implicate myelin-related systems involved in NBIA neuropathogenesis in early responses to iron loading. This may contribute to behavioral symptoms in NBIA and hemochromatosis and is relevant to patients with abnormal iron status and psychiatric disorders involving myelin abnormalities or resistant to conventional treatments.
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.
authors.forename: M
authors.initials: M
authors.lastname: Heidari
authors.affiliation: Bosch Institute and Discipline of Physiology, University of Sydney, Sydney, NSW, Australia.
authors.forename: D M
authors.initials: DM
authors.lastname: Johnstone
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.
authors.forename: B
authors.initials: B
authors.lastname: Bassett
authors.affiliation: School of Biomedical Sciences and Curtin Health Innovation Research Institute - Biosciences, Curtin University of Technology, Bentley, WA, Australia.
authors.forename: R M
authors.initials: RM
authors.lastname: Graham
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fiona Stanley Hospital, Murdoch, WA, Australia.|Harry Perkins Institute of Medical Research, Murdoch, WA, Australia.
authors.forename: A C G
authors.initials: AC
authors.lastname: Chua
authors.affiliation: School of Physics, University of Western Australia, Crawley, WA, Australia.
authors.forename: M J
authors.initials: MJ
authors.lastname: House
authors.affiliation: Warwick Engineering in Biomedicine, School of Engineering, University of Warwick, Coventry, UK.
authors.forename: J F
authors.identifier: 0000-0001-9090-7690
authors.initials: JF
authors.lastname: Collingwood
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Bettencourt
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: H
authors.initials: H
authors.lastname: Houlden
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.|Department of Medical and Molecular Genetics, King's College London, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Ryten
authors.affiliation: School of Biomedical Sciences and Curtin Health Innovation Research Institute - Biosciences, Curtin University of Technology, Bentley, WA, Australia.|Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia.|Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, The University of Western Australia, Murdoch, WA, Australia.|Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, WA, Australia.
authors.forename: J K
authors.initials: JK
authors.lastname: Olynyk
authors.affiliation: School of Medicine and Pharmacology, University of Western Australia, Fiona Stanley Hospital, Murdoch, WA, Australia.|Harry Perkins Institute of Medical Research, Murdoch, WA, Australia.
authors.forename: D
authors.initials: D
authors.lastname: Trinder
authors.affiliation: School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, Australia.
authors.forename: E A
authors.initials: EA
authors.lastname: Milward
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D015870:Gene Expression; D006432:Hemochromatosis / Q000235:genetics / Q000378:metabolism; D000071020:Hemochromatosis Protein / Q000378:metabolism / Q000502:physiology; D007501:Iron / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism; D019189:Iron Metabolism Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008806:Mice, Inbred AKR; D009186:Myelin Sheath / Q000378:metabolism; D019150:Neuroaxonal Dystrophies / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D010375:Pedigree; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism
chemical_list: D000071020:Hemochromatosis Protein; D008565:Membrane Proteins; D011990:Receptors, Transferrin; C503641:TFR2 protein, mouse; D007501:Iron