title: Impaired iron homeostasis in Parkinson's disease.
abstract: Despite physiological systems designed to achieve iron homeostasis, increased concentrations of brain iron have been demonstrated in a range of neurodegenerative diseases. These including the parkinsonian syndromes, the trinucleotide repeat disorders and the dementia syndromes. The increased brain iron is confined to those brain regions most affected by the degeneration characteristic of the particular disorder and is suggested to stimulate cell damage via oxidative mechanisms. Changes in central iron homeostasis have been most closely investigated in PD, as this disorder is well characterised both clinically and pathologically. PD is associated with a significant increase in iron in the degenerating substantia nigra (SN) and is measureable in living PD patients and in post-mortem brain. This increase, however, occurs only in the advanced stages of the disease, suggesting that this phenonoma may be a secondary, rather than a primary initiating event, a hypothesis also supported by evidence from animal experiments. The source of the increased iron is unknown but a variety of changes in iron homeostasis have been identified in PD, both in the brain and in the periphery. The possibility that an increased amount of iron may be transported into the SN is supported by data demonstrating that one form of the iron-binding glycoprotein transferrin family, lactotransferrin, is increased in surviving neurons in the SN in the PD brain and that this change is associated with increased numbers of lactotransferrin receptors on neurons and microvessels in the parkinsonian SN. These changes could represent one mechanism by which iron might concentrate within the PD SN. Alternatively, the measured increased in iron might result from a redistribution of ferritin iron stores. Ferritin is located in glial cells while the degenerating neurons do not stain positive for ferritin. As free radicals are highly reactive, it is unlikely that glial-derived free radicals diffuse across the intracellular space in sufficent quantities to damage neuronal constituents. If intracellular iron release contributes to neuronal damage it seems more probable that an intraneuronal iron source is responsible for oxidant-mediated damage. Such a iron source is neuromelanin (NM), a dark-coloured pigment found in the dopaminergic neurons of the human SN. In the normal brain, NM has the ability to bind a variety of metals, including iron, and increased NM-bound iron is reported in the parkinsonian SN. The consequences of these phenomena for the cell have not yet been clarified. In the absence of significant quantities of iron NM can act as an antioxidant, in that it can interact with and inactivate free radicals. On the other hand, in the presence of iron NM appears to act as a proxidant, increasing the rate of free radical production and thus the oxidative load within the vulnerable neurons. Given that increased iron is only apparent in the advanced stages of the disease it is unlikely that NM is of importance for the primary aetiology of PD. A localised increase in tissue iron and its interaction with NM may be, however, important as a secondary mechanism by increasing the oxidative load on the cell, thereby driving neurodegeneration.
authors.affiliation: Prince of Wales Medical Research Institute, Sydney, NSW, Australia. K.Double@unsw.edu.au
authors.forename: K L
authors.initials: KL
authors.lastname: Double
authors.forename: M
authors.initials: M
authors.lastname: Gerlach
authors.forename: M B
authors.initials: MB
authors.lastname: Youdim
authors.forename: P
authors.initials: P
authors.lastname: Riederer
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D007501:Iron