Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia

Dexter, David T.; Jenner, Peter; Schapira, Anthony H. V.; Marsden, C. D.

doi:10.1002/ana.410320716

Cited by 287 publications

(135 citation statements)

References 22 publications

(4 reference statements)

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“…Brain iron accumulation in association with neurologic symptoms has been observed in Hallervorden-Spatz disease, but the mechanisms of iron accumulation in the basal ganglia of these patients and the relationship of this to clinical symptoms is unknown (46). A direct role for iron-mediated tissue injury in the brain is supported by studies on the role of this metal in oxidant-mediated ischemia-reperfusion injury after stroke and cerebral hemorrhage and by data which demonstrate marked abnormalities in iron metabolism in a number of neurodegenerative disorders (47). In this regard, previous studies have revealed age-related decreases in human ceruloplasmin oxidase activity in the plasma, making it reasonable to speculate that such changes in the brain, in association with other environmental or genetic factors, may contribute to neurodegeneration observed with aging (48).…”

Section: Discussionmentioning

confidence: 99%

Ceruloplasmin gene expression in the murine central nervous system.

Klomp¹,

Farhangrazi²,

Dugan³

et al. 1996

J. Clin. Invest.

182

131

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Aceruloplasminemia is an autosomal recessive disorder resulting in neurodegeneration of the retina and basal ganglia in association with iron accumulation in these tissues. To begin to define the mechanisms of central nervous system iron accumulation and neuronal loss in this disease, cDNA clones encoding murine ceruloplasmin were isolated and characterized. RNA blot analysis using these clones detected a 3.7-kb ceruloplasmin-specific transcript in multiple murine tissues including the eye and several regions of the brain. In situ hybridization of systemic tissues revealed cellspecific ceruloplasmin gene expression in hepatocytes, the splenic reticuloendothelial system and the bronchiolar epithelium of the lung. In the central nervous system, abundant ceruloplasmin gene expression was detected in specific populations of astrocytes within the retina and the brain as well as the epithelium of the choroid plexus. Analysis of primary cell cultures confirmed that astrocytes expressed ceruloplasmin mRNA and biosynthetic studies revealed synthesis and secretion of ceruloplasmin by these cells. Taken together these results demonstrate abundant cell-specific ceruloplasmin expression within the central nervous system which may account for the unique clinical and pathologic findings observed in patients with aceruloplasminemia. ( J. Clin. Invest. 1996. 98:207-215)

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Section: Discussionmentioning

confidence: 99%

Ceruloplasmin gene expression in the murine central nervous system.

Klomp¹,

Farhangrazi²,

Dugan³

et al. 1996

J. Clin. Invest.

182

131

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“…Ferritin is the major iron storage protein in the body which maintains iron in a nonreactive form in the cell. Results from several studies suggest that ferritin in the SNpc is not increased concomitantly with iron (26). Although it has been previously speculated that increasing iron loading by ferritin may increase the risk of free radical damage to the cell (27), a recent in vivo study has shown that genetically enhanced expression of ferritin and pharmacological iron chelation (clioquinol) prevents MPTP-induced neurotoxicity (28).…”

Section: Role Of Iron In Pd Pathogenesismentioning

confidence: 99%

Interactions Between Environmental and Genetic Factors in the Pathophysiology of Parkinson's Disease

Tsang¹,

Soong²

2003

IUBMB Life

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SummaryParkinson's disease (PD) is a progressive neurodegenerative disease with no known cure and affects approximately 1% of the elderly population. The major question in PD relates to the selective loss of dopaminergic neurons in patients. The underlying mechanism of genetic dysfunction and environmental toxins in contributing to the pathogenesis of PD may be oxidative stress. The interactions of genetic and environmental factors in PD may provide some answers to the longstanding question. In particular, the possibility that iron may provide selectivity to genetic susceptibility or dopamine reactivity in dopaminergic neuronal death is enhanced by the neuroprotection demonstrated in transgenic mice overexpressing ferritin or the use of iron chelators in MPTP-induced PD mouse. It will be important to dissect and understand the contributions of genes, environment and intrinsic cellular states in the generation and progression of the pathophysiology of PD.

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“…In human nigral neurons the level of H-Frt is relatively low [2,26], and in PD the Frt level remained unchanged in the SN where the total iron level is increased [45]. H-Frt is degraded via both UPS and the autophagy-lysosome pathway [44,46].…”

Section: Discussionmentioning

confidence: 99%

A Mechanistic Study of Proteasome Inhibition-Induced Iron Misregulation in Dopamine Neuron Degeneration

Xie

Zhang

et al. 2012

Neurosignals

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Ubiquitin proteasome system (UPS) impairment and iron misregulation have been implicated in dopamine (DA) neuron degeneration in Parkinson’s disease. As previously shown, proteasome inhibition in a rodent model can cause nigral neuron degeneration accompanied by iron accumulation. To investigate the involvement of iron in DA neuron degeneration, we generated an in vitro model by applying proteasome inhibitor lactacystin in DAergic cell line MES23.5 culture. We found that lactacystin caused marked increase in labile iron, reactive oxygen species and ubiquitin-conjugated protein aggregation prior to cell injury. These effects were attenuated by iron chelators or antioxidants. Furthermore, we demonstrated that the iron regulatory protein (IRP)/iron response element system contributed to UPS impairment-mediated DA neuron injury. We documented that IRP2 disruption resulted in an increase in transferrin receptor 1 (TfR1), a decrease in ferritin heavy chain (H-Frt), and eventually cell death. These findings provide insight into the mechanistic interplay between UPS impairment and iron misregulation and suggest that the disturbances in IRP2, TfR1 and H-Frt may contribute to DA neuron degeneration.

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Alterations in levels of iron, ferritin, and other trace metals in neurodegenerative diseases affecting the basal ganglia

Cited by 287 publications

References 22 publications

Ceruloplasmin gene expression in the murine central nervous system.

Ceruloplasmin gene expression in the murine central nervous system.

Interactions Between Environmental and Genetic Factors in the Pathophysiology of Parkinson's Disease

A Mechanistic Study of Proteasome Inhibition-Induced Iron Misregulation in Dopamine Neuron Degeneration

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