title: Hephaestin and ceruloplasmin play distinct but interrelated roles in iron homeostasis in mouse brain.
abstract: BACKGROUND
  Iron accumulation in the central nervous system (CNS) is a common feature of many neurodegenerative diseases. Multicopper ferroxidases (MCFs) play an important role in cellular iron metabolism. However, the role of MCFs in the CNS in health and disease remains poorly characterized.
  
  
  OBJECTIVE
  The aim was to study the role of hephaestin (HEPH) and ceruloplasmin (CP) in CNS iron metabolism and homeostasis.
  
  
  METHODS
  Iron concentrations and L-ferritin protein levels of selected brain regions were determined in global hephaestin knockout (Heph KO), global ceruloplasmin knockout (Cp KO), and wild-type (WT) male mice at 6-7 mo of age. Gene expression of divalent metal transporter 1 (Dmt1), ferroportin 1 (Fpn1), Heph, Cp, and transferrin receptor 1 (Tfrc) and HEPH protein level was quantitated in the same brain regions.
  
  
  RESULTS
  Iron and L-ferritin protein levels were significantly increased in Heph KO mouse brain cortex (iron: 30%, P < 0.05; L-ferritin: 200%, P < 0.05), hippocampus (iron: 80%, P < 0.05; L-ferritin: 300%, P < 0.05), brainstem (iron: 20%, P < 0.05; L-ferritin: 150%, P < 0.05), and cerebellum (iron: 20%, P < 0.05; L-ferritin: 100%, P < 0.05) regions than in WT and Cp KO mouse brain regions at 6 mo of age. Expression of the Heph gene was significantly increased in the Cp KO mouse cortex (100%; P < 0.01), hippocampus (350%; P < 0.001), brainstem (30%; P < 0.01), and cerebellum (150%; P < 0.001) than in WT controls, and Cp gene expression was significantly decreased in the Heph KO mouse hippocampus (20%; P < 0.05) than in WT control mice at 6 mo of age.
  
  
  CONCLUSIONS
  Ablation of HEPH or CP results in disordered brain iron homeostasis in mice. Heph KO may provide a novel model for neurodegenerative disorders.
authors: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China;
authors: Ruiwei
authors: R
authors: Jiang
authors: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China;
authors: Chao
authors: C
authors: Hua
authors: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China;
authors: Yike
authors: Y
authors: Wan
authors: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China;
authors: Bo
authors: B
authors: Jiang
authors: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China;
authors: Huiyin
authors: H
authors: Hu
authors: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China;
authors: Jiashuo
authors: J
authors: Zheng
authors: Department of Nutritional Science and Toxicology, University of California, Berkeley, CA; Berghofer Medical Research Institute, Brisbane, Australia;
authors: Brie K
authors: BK
authors: Fuqua
authors: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA; and.
authors: Joshua L
authors: JL
authors: Dunaief
authors: Berghofer Medical Research Institute, Brisbane, Australia;
authors: Gregory J
authors: GJ
authors: Anderson
authors: Center for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Canada.
authors: Samuel
authors: S
authors: David
authors: Department of Nutritional Science and Toxicology, University of California, Berkeley, CA;
authors: Chris D
authors: CD
authors: Vulpe
authors: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China; hjchen@nju.edu.cn.
authors: Huijun
authors: H
authors: Chen
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D002570:Ceruloplasmin / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D027682:Cation Transport Proteins; D002570:Ceruloplasmin; D007501:Iron; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011990:Receptors, Transferrin; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C117324:Heph protein, mouse; C480029:Tfrc protein, mouse
keywords: brain; ceruloplasmin; ferroxidase activity; hephaestin; iron accumulation