Iron and Neurodegeneration: From Cellular Homeostasis to Disease

Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, EAN, Oeiras, Portugal.
Oxidative Medicine and Cellular Longevity (Impact Factor: 3.36). 05/2012; 2012(1):128647. DOI: 10.1155/2012/128647
Source: PubMed


Accumulation of iron (Fe) is often detected in the brains of people suffering from neurodegenerative diseases. High Fe concentrations have been consistently observed in Parkinson’s, Alzheimer’s, and Huntington’s diseases; however, it is not clear whether this Fe contributes to the progression of these diseases. Other conditions, such as Friedreich’s ataxia or neuroferritinopathy are associated with genetic factors that cause Fe misregulation. Consequently, excessive intracellular Fe increases oxidative stress, which leads to neuronal dysfunction and death. The characterization of the mechanisms involved in the misregulation of Fe in the brain is crucial to understand the pathology of the neurodegenerative disorders and develop new therapeutic strategies.
Saccharomyces cerevisiae
, as the best understood eukaryotic organism, has already begun to play a role in the neurological disorders; thus it could perhaps become a valuable tool also to study the metalloneurobiology.

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    • "Thus, altered CNS iron metabolism is likely to initiate or contribute to the development of neurodegenerative diseases, such FXTAS. Iron dysregulation has been linked to a series of neurodegenerative disease, including Parkinson and Alzheimer diseases, amyotrophic lateral sclerosis, restless legs syndrome, and prion diseases (Batista-Nascimento et al., 2012). Indeed, Parkinsonism and dementia are common in those with FXTAS (Hagerman and Hagerman, 2013; Tassone et al., 2012), and restless legs syndrome is more common in those with the premutation compared to controls (Summers et al., 2014). "
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    ABSTRACT: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene that is characterized by progressive action tremor, gait ataxia, and cognitive decline. Recent studies of mitochondrial dysfunction in FXTAS have suggested that iron dysregulation may be one component of disease pathogenesis. We tested the hypothesis that iron dysregulation is part of the pathogenic process in FXTAS. We analyzed postmortem choroid plexus from FXTAS and control subjects, and found that in FXTAS iron accumulated in the stroma, transferrin levels were decreased in the epithelial cells, and transferrin receptor 1 distribution was shifted from the basolateral membrane (control) to a predominantly intracellular location (FXTAS). In addition, ferroportin and ceruloplasmin were markedly decreased within the epithelial cells. These alterations have implications not only for understanding the pathophysiology of FXTAS, but also for the development of new clinical treatments that may incorporate selective iron chelation. Copyright © 2014. Published by Elsevier B.V.
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    • "Elements influencing the development of diabetes mellitus and a number of neurodegenerative disorders have been well established (see reviews [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]), however, given their complexity, a succinct analysis of major underlying themes spanning them has yet to be presented. Approximately 60–70% of the 25.8 million Americans with diabetes develop neurological symptoms and damage [17]. "
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    • "In order to enter the brain, Fe needs to cross two distinct barriers , the blood–brain barrier and the blood–cerebrospinal barrier (Pardridge et al., 1987; Zheng and Monnot, 2012). Fe-related neurodegenerative disorders can result from both Fe accumulation or defects in its metabolism and/or homeostasis (Batista-Nascimento et al., 2012). Brain tissue is thought to be more susceptible to ROS-dependent damage than other organs, a feature associated with (i) the fact that neurons are enriched in mitochondria and possess a rather high aerobic metabolism; (ii) the low levels of some antioxidant enzymes; (iii) the high content of polyunsaturated fatty acids in brain membranes; and (iv) the high Fe content, which may combine their effects to make the brain a preferential target for oxidative stress-related degeneration (Halliwell, 2006). "
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