Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases

Moones Heidari; Sam H Gerami; Brianna Bassett; Ross M Graham; Anita C G Chua; Ritambhara Aryal; Michael J House; Joanna F Collingwood; Conceição Bettencourt; Henry Houlden; Mina Ryten; UK Brain Expression Consortium (UKBEC); John K Olynyk; Debbie Trinder; Daniel M Johnstone; Elizabeth A Milward

doi:10.1080/21675511.2016.1198458

Pathological relationships involving iron and myelin may constitute a shared mechanism linking various rare and common brain diseases

Rare Dis. 2016 Jun 22;4(1):e1198458. doi: 10.1080/21675511.2016.1198458. eCollection 2016.

Authors

Moones Heidari¹, Sam H Gerami¹, Brianna Bassett¹, Ross M Graham², Anita C G Chua³, Ritambhara Aryal¹, Michael J House⁴, Joanna F Collingwood⁵, Conceição Bettencourt⁶, Henry Houlden⁷, Mina Ryten⁸; UK Brain Expression Consortium (UKBEC); John K Olynyk⁹, Debbie Trinder³, Daniel M Johnstone¹⁰, Elizabeth A Milward¹

Affiliations

¹ School of Biomedical Sciences and Pharmacy, The University of Newcastle , Callaghan, NSW, Australia.
² School of Biomedical Sciences & Curtin Health Innovation Research Institute - Biosciences, Curtin University of Technology , Bentley, WA, Australia.
³ School of Medicine and Pharmacology, University of Western Australia, Fiona Stanley Hospital, Murdoch, WA, Australia; Harry Perkins Institute of Medical Research, Murdoch, WA, Australia.
⁴ School of Physics, University of Western Australia , Crawley, WA, Australia.
⁵ Warwick Engineering in Biomedicine, School of Engineering, University of Warwick , Coventry, UK.
⁶ Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, London, UK.
⁷ Department of Molecular Neuroscience, UCL Institute of Neurology , London, UK.
⁸ Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Department of Medical and Molecular Genetics, King's College London, London, UK.
⁹ School of Biomedical Sciences & 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, Murdoch, WA, Australia; Department of Gastroenterology and Hepatology, Fremantle Hospital, Fremantle, WA, Australia.
¹⁰ Bosch Institute and Discipline of Physiology, University of Sydney , Sydney, NSW, Australia.

Abstract

We previously demonstrated elevated brain iron levels in myelinated structures and associated cells in a hemochromatosis Hfe (-/-) xTfr2 (mut) mouse model. This was accompanied by altered expression of a group of myelin-related genes, including a suite of genes causatively linked to the rare disease family 'neurodegeneration with brain iron accumulation' (NBIA). Expanded data mining and ontological analyses have now identified additional myelin-related transcriptome changes in response to brain iron loading. Concordance between the mouse transcriptome changes and human myelin-related gene expression networks in normal and NBIA basal ganglia testifies to potential clinical relevance. These analyses implicate, among others, genes linked to various rare central hypomyelinating leukodystrophies and peripheral neuropathies including Pelizaeus-Merzbacher-like disease and Charcot-Marie-Tooth disease as well as genes linked to other rare neurological diseases such as Niemann-Pick disease. The findings may help understand interrelationships of iron and myelin in more common conditions such as hemochromatosis, multiple sclerosis and various psychiatric disorders.

Keywords: NBIA; array; brain; hemochromatosis; iron; myelin; neurodegeneration; oligodendrocyte.

Abstract

Grants and funding