Molecular genetic approaches to understanding the roles and regulation of iron in brain health and disease

Abstract

Abbreviations used: IRE, iron-responsive element; IRP, iron regulatory protein; MRI, magnetic resonance imaging; NBIA, neurodegeneration with brain iron accumulation; PANK2, pantothenate kinase 2. AbstractIron is essential in the brain, yet too much iron can be toxic. Tight regulation of iron in the brain may involve intrinsic mechanisms that control internal homeostasis independent of systemic iron status. Iron abnormalities occur in various neurological disorders, usually with symptoms or neuropathology associated with movement impairment or behavioral disturbances rather than cognitive impairment or dementia. Consistent with this, polymorphisms in the HFE gene, associated with the iron overload disorder hemochromatosis, show stronger associations with the movement disorder amyotrophic lateral sclerosis (motor neuron disease) than with cognitive impairment. Such associations may arise because certain brain regions involved in movement or executive control are particularly iron-rich, notably the basal ganglia, and may be highly reliant on iron. Various mechanisms, including iron redistribution causing functional iron deficiency, lysosomal and mitochondrial abnormalities or oxidative damage, could underlie iron-related neuropathogenesis. Clarifying how iron contributes causatively to neurodegeneration may improve treatment options in a range of neurodegenerative disorders. This review considers how modern molecular genetic approaches can be applied to resolve the complex molecular systems and pathways by which brain iron homeostasis is regulated and the molecular changes that occur with iron dyshomeostasis and neuropathogenesis.

Brain transcriptome perturbations in the transferrin receptor 2 mutant mouse support the case for brain changes in iron loading disorders, including effects relating to long-term depression and long-term potentiation

“…Iron has crucial roles in brain functions such as neurotransmitter synthesis and myelination but abnormally high brain iron levels have been proposed to be associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and neurodegeneration with brain iron accumulation (reviewed (Johnstone and Milward, 2010b)). However debate surrounds the question of whether disorders of systemic iron accumulation, such as hereditary hemochromatosis, can also have detrimental effects on the brain.…”

Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis

“…Iron homeostasis dysregulation has been regarded as an important mechanism in neurodegeneration and particularly in ALS [12]. The HFE protein plays an important role in iron homeostasis, by participating in the regulation of iron uptake.…”

Change in the characteristics of ferritin induces iron imbalance in prion disease affected brains

“…However, mounting evidence suggests that the change in brain iron precedes neuronal degeneration, and is often the main trigger for neurotoxicity. Specific examples include inherited disorders of brain iron imbalance such as neurodegeneration with brain iron accumulation, neuroferritinopathy, infantile neuroaxonal dystrophy-1, aceruloplasminemia, Friedreich’s ataxia, and Restless Leg Syndrome (RLS) (Johnstone and Milward, 2010). A similar association between iron imbalance and neurotoxicity is less clear for sporadic disorders.…”