The Role of Iron in Neurodegeneration

Iron has a double effect on cells: it is an essential element required for many biological reactions but, on the other hand, its excess could be toxic, resulting in the generation of reactive oxygen species. In this review we discuss how different cell types manage iron homeostasis in order to provide iron where it is needed and avoiding its toxicity. Iron management in the body starts at the level of its absorption through enterocytes, but also involves its utilization in erythroid cells, storage/mobilization in hepatocytes and recycling from macrophages. The maintenance of appropriate iron homeostasis is also important for brain cells. Here we review more recent hypotheses on mechanisms of brain iron homeostasis under normal conditions: how iron is imported from the blood circulation, redistributed through the brain and stored in neurons and other cells of the central nervous system is described carefully. However, iron accumulation and overload in the brain is commonly associated with neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's diseases (AD): iron accumulates in specific brain regions targeted by these severe diseases, increasing the oxidative-induced neuronal vulnerability. The major risk factor for AD and PD remains brain aging, while genetic components account only for a minor part of these diseases. Iron increases with aging in several brain regions. Mutations in genes encoding proteins involved in iron, leading to iron accumulation, occur in other diseases such as neuroferritinopathy, neurodegeneration with brain iron accumulation, Friedreich's ataxia and aceruloplasminemia. Molecular understanding of iron accumulation in normal, aged and pathological brain may be helpful in identifying new pharmacological targets to improve iron management.