Centre for Neuroscience - Theses
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ItemMechanisms of brain iron homeostasis involved in Parkinson's disease( 2011)Parkinson’s disease (PD) is a neurodegenerative disorder characterised by motor deficits accompanying degeneration of Substantia Nigra (SN) neurons. Although familial forms of the disease exist, the cause of sporadic PD is unknown. Symptomatic treatments are available for PD, but there are no disease modifying therapies. The degenerating SN exhibits iron accumulation, commonly thought to participate in neurodegeneration. The cause of iron accumulation in PD has not been established; hence, the aim of this thesis was to investigate the mechanism of iron accumulation in PD. A battery of proteins regulates cellular iron import, storage and export. Described in this thesis is an investigation of possible mechanisms of iron elevation in PD. The experiments included in this thesis involved analysis of post mortem tissue, as well as tissue culture and animal models. It was hypothesised that altered cellular uptake or release of iron contributes to iron pathology in PD. Evidence obtained in this investigation was used to argue that stimulation of the cellular iron import pathway cannot alone account for iron accumulation in PD. It was therefore hypothesised that a failure of iron export mediates iron accumulation in PD. Proteins involved with iron export (Ferroportin, Ceruloplasmin, amyloid precursor protein (APP), transferrin) were found to be decreased in PD afflicted human brain, and in an animal model of PD, providing evidence for disturbed iron export activity in PD. In pursuit of iron export correction, peripheral administration of transferrin was investigated as a potential iron attenuating therapeutic. In addition, the amine oxidase activity of APP was explored, with implications for PD. It was hypothesised that in PD, there is disturbed regulation of the proteins that serve to maintain iron homeostasis. By surveying brain tissue, iron levels were found to be correlated with several iron associated proteins in control tissue, however, in contrast, almost all iron-associated proteins lose their correlation with the iron levels in PD tissue. This possibly suggests that in PD, the brain becomes insensitive to the cellular iron content, thus making it susceptible to iron accumulation through loss of homeostasis. A possible mechanism for iron dyshomeostasis is via altered Nitric oxide (NO) signalling. NO is a cell-signalling molecule extensively linked to PD; NO is elevated in PD and thought to participate in nitrative stress by reaction with the superoxide molecule to form the highly reactive peroxynitrite radical. NO also disturbs iron regulation by manipulating iron responsive proteins 1 and 2, as well as hypoxia inducing factor 1α which, in concert, govern iron homeostasis. It was hypothesised that NO elevation in PD is the mechanism for perturbed regulation of iron. Preventing NO induction in an animal model of PD restored iron regulation, prevented iron accumulation, and protected against toxicity. It was concluded that iron accumulation in PD is contributed by the dysregulation of iron-associated proteins, particularly those associated with iron export. NO is the likely upstream molecule that causes this iron perturbation in PD.