Research Report Brain transcriptome perturbations in the Hfe -/- mouse model of genetic iron loading Daniel Johnstone a, b, c , d, e , Ross M. Graham f , g, h , Debbie Trinder f , g , Roheeth D. Delima f , g , Carlos Riveros b, c , d , John K. Olynyk f , g, i , j , Rodney J. Scott a, b, c , k , Pablo Moscato b, c , d , Elizabeth A. Milward a, b, c , ⁎ a School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, Australia b Hunter Medical Research Institute, New Lambton Heights, Australia c Centre for Bioinformatics, Biomarker Discovery and Information-Based Medicine, The University of Newcastle, Callaghan, Australia d School of Electrical Engineering and Computer Science, The University of Newcastle, Callaghan, Australia e Bosch Institute and Discipline of Physiology, University of Sydney, Sydney, Australia f School of Medicine and Pharmacology, University of Western Australia, Fremantle, Australia g Western Australian Institute for Medical Research, Perth, Australia h School of Biomedical Sciences, Curtin University of Technology, Bentley, Australia i Curtin Health Innovation Research Institute, Curtin University of Technology, Bentley, Australia j Department of Gastroenterology, Fremantle Hospital, Fremantle, Australia k Division of Genetics, Hunter Area Pathology Service, John Hunter Hospital, Newcastle, New South Wales, Australia ARTICLE INFO ABSTRACT Article history: Accepted 2 February 2012 Available online 9 February 2012 Severe disruption of brain iron homeostasis can cause fatal neurodegenerative disease, however debate surrounds the neurologic effects of milder, more common iron loading disorders such as hereditary hemochromatosis, which is usually caused by loss-of-function polymorphisms in the HFE gene. There is evidence from both human and animal studies that HFE gene variants may affect brain function and modify risks of brain disease. To investigate how disruption of HFE influences brain transcript levels, we used microarray and real-time reverse transcription polymerase chain reaction to assess the brain transcriptome in Hfe -/- mice relative to wildtype AKR controls (age 10 weeks, n ≥ 4/group). The Hfe -/- mouse brain showed numerous significant changes in transcript levels (p < 0.05) although few of these related to proteins directly involved in iron homeostasis. There were robust changes of at least 2-fold in levels of transcripts for prominent genes relating to transcriptional regulation (FBJ osteosarcoma oncogene Fos, early growth response genes), neurotransmission (glutamate NMDA receptor Grin1, GABA receptor Gabbr1) and synaptic plasticity and memory (calcium/calmodulin-depen- dent protein kinase IIα Camk2a). As previously reported for dietary iron-supplemented mice, there were altered levels of transcripts for genes linked to neuronal ceroid lipofuscinosis, a disease characterized by excessive lipofuscin deposition. Labile iron is known to enhance lipofuscin generation which may accelerate brain aging. The findings provide evidence that iron loading disorders can considerably perturb levels of transcripts for genes essential for Keywords: Iron Hemochromatosis HFE Microarray Mouse model BRAIN RESEARCH 1448 (2012) 144 – 152 ⁎ Corresponding author at: School of Biomedical Sciences and Pharmacy MSB, The University of Newcastle, Callaghan, NSW 2308, Australia. Fax: +61 2 4921 7903. E-mail address: Liz.Milward@newcastle.edu.au (E.A. Milward). 0006-8993/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.brainres.2012.02.006 Available online at www.sciencedirect.com www.elsevier.com/locate/brainres