Key Points
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Iron homeostasis in the CNS operates in parallel with systemic iron homeostasis, because iron must cross the blood–brain barrier or blood–cerebrospinal fluid barrier to enter the CNS.
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Oligodendrocytes within the CNS synthesize transferrin, and most CNS cells acquire iron through transferrin receptor 1 in concert with the iron transporter divalent metal transporter 1 (DMT1).
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Neurons in the globus pallidus are unusually rich in ferritin and iron, containing iron at levels comparable to those in the liver, the systemic iron repository.
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In the CNS, astrocytes depend on glycosyl phosphatidylinisotol (GPI)-linked ceruloplasmin generated by alternative splicing to facilitate iron export by ferroportin.
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MRI has revolutionized neurological diagnostics by detecting specific regional iron overload in the brains of patients with movement disorders and thereby characterizing rare types of specific inherited diseases.
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Thus far, nine neurodegeneration with brain iron accumulation (NBIA) disease genes have been identified, two of which are caused by mutations in known iron metabolism proteins that result in aceruloplasminaemia and neuroferritinopathy.
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Identification of other NBIA disease genes has not yet led to recognition of a common pathogenic pathway, but recent studies have shown defects of mitochondrial cristae in models of two of the most common diseases, pantothenate kinase-associated neurodegeneration (PKAN) and phospholipase A2, group VI (PLA2G6)-associated neurodegeneration (PLAN), suggesting that defective cardiolipin synthesis or maintenance may be a common feature.
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Perivascular iron accumulation and astrocytic iron overload have been described in PKAN and mitochondrial membrane-associated neurodegeneration (MPAN), raising the possibility that astrocytic chemosensing of metabolic distress from diseased brain regions may convey signals to the blood–brain barrier, which cause increased uptake of nutrients such as iron as part of a regulatory response designed to counteract energy failure in dying neurons.
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Iron chelators have been used successfully to prevent retinal degeneration in ferroxidase-deficient mice, but in some diseases, neurons may die from iron deficiency rather than iron overload, and the iron overload noted in some diseases may be attributable to activation and influx of microglia into the area of neurodegeneration.
Abstract
Abnormal accumulation of brain iron has been detected in various neurodegenerative diseases, but the contribution of iron overload to pathology remains unclear. In a group of distinctive brain iron overload diseases known as 'neurodegeneration with brain iron accumulation' (NBIA) diseases, nine disease genes have been identified. Brain iron accumulation is observed in the globus pallidus and other brain regions in NBIA diseases, which are often associated with severe dystonia and gait abnormalities. Only two of these diseases, aceruloplasminaemia and neuroferritinopathy, are directly caused by abnormalities in iron metabolism, mainly in astrocytes and neurons, respectively. Understanding the early molecular pathophysiology of these diseases should aid insights into the role of iron and the design of specific therapeutic approaches.
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Acknowledgements
The author thanks S. Hayflick and R. Vidal for generously sharing images. The author gratefully acknowledges that the intramural programme of the Eunice Kennedy Shriver National Institute of Child Health and Human Development supported this work.
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Rouault, T. Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 14, 551–564 (2013). https://doi.org/10.1038/nrn3453
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DOI: https://doi.org/10.1038/nrn3453
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