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

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:

• array
• brain
• hemochromatosis
• iron
• myelin
• neurodegeneration
• NBIA
• oligodendrocyte

This article refers to:

Abbreviations

CNS	=	central nervous system
DAB	=	3,3′-diaminobenzidine
FC	=	fold change
MIM	=	Mendelian Inheritance in Man
NBIA	=	neurodegeneration with brain iron accumulation

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors would like to thank the UK Brain Expression Consortium affiliated with the UCL Institute of Neurology, King's College London, Istituto di Ricerca Genetica e Biomedica, CNR, Cagliari and the University of Edinburgh; LN Hazrati for assistance with provision of tissue from the Canadian Brain Tissue Bank (University of Toronto, Canada) and the Newcastle Brain Tissue Resource, supported by the MRC, the Alzheimer Research Trust and Alzheimer Society through the Brains for Dementia Research Initiative and NIHR Biomedical Research Center grants.

Funding

This study was supported by the National Health and Medical Research Council of Australia (572601, 1042370, 1020437, 1078747), Fremantle Hospital Medical Research Foundation, Australian Society for Medical Research, EPSRC (EP/D066654/1), the UK Medical Research Council (MR/J004758/1) and the Wellcome Trust (WT104033/Z/14/Z).