Expression of a membrane‐bound form of the ferroxidase ceruloplasmin by leptomeningeal cells

Mittal, Bina; Doroudchi, Mohammad M.; Jeong, Suh Young; Patel, Bharatkumar N.; David, Samuel

doi:10.1002/glia.10158

Cited by 37 publications

(19 citation statements)

References 43 publications

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“…Frequent neurological manifestations in WD patients indicate that ATP7B is important for normal CNS function, yet little is known about the specific role of ATP7B in any region of the brain, although basal ganglia seems to be most affected by ATP7B inactivation. Ceruloplasmin, the protein that receives copper from ATP7B in the liver (see above), is also expressed in the brain [16][17][18]. In mice, both ATP7B and ceruloplasmin are detected in Purkinje neurons [16][17][18][19], thus it seems likely that one of the functions of ATP7B is to supply copper to ceruloplasmin.…”

Section: The Role Of Atp7b In Mammalian Physiologymentioning

confidence: 95%

Atp7b −/− mice as a model for studies of Wilson's disease

Lutsenko

2008

Biochemical Society Transactions

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Wilson's disease is a severe human disorder of copper homoeostasis. The disease is associated with various mutations in the ATP7B gene that encodes a copper-transporting ATPase, and a massive accumulation of copper in the liver and several other tissues. The most frequent disease manifestations include a wide spectrum of liver pathologies as well as neurological and psychiatric abnormalities. A combination of copper chelators and zinc therapy has been used to prevent disease progression; however, accurate and timely diagnosis of the disease remains challenging. Similarly, side effects of treatments are common. To understand better the biochemical and cellular basis of Wilson's disease, several animal models have been developed. This review focuses on genetically engineered Atp7b(-/-) mice and describes the properties of these knockout animals, insights into the disease progression generated using Atp7b(-/-) mice, as well as advantages and limitations of Atp7b(-/-) mice as an experimental model for Wilson's disease.

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Section: The Role Of Atp7b In Mammalian Physiologymentioning

confidence: 95%

Atp7b −/− mice as a model for studies of Wilson's disease

Lutsenko

2008

Biochemical Society Transactions

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“…One of these proteins is the copper protein ceruloplasmin (Cp), which is secreted by the liver into plasma, and by cells of the choroid plexus into CSF (Vassiliev et al, 2005). A membranebound glycosylphosphatidylinositol (GPI)-anchored form of Cp is expressed by astrocytes and by leptomeningeal cells in the CNS (Mittal et al, 2003). Cp acts as a ferroxidase, one that oxidizes toxic ferrous iron to the nontoxic ferric form (Hellman and Gitlin, 2002).…”

Section: Introductionmentioning

confidence: 99%

Ceruloplasmin Oxidation, a Feature of Parkinson's Disease CSF, Inhibits Ferroxidase Activity and Promotes Cellular Iron Retention

Olivieri

Conti²,

Iannaccone³

et al. 2011

J. Neurosci.

119

114

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Parkinson's disease is a neurodegenerative disorder characterized by oxidative stress and CNS iron deposition. Ceruloplasmin is an extracellular ferroxidase that regulates cellular iron loading and export, and hence protects tissues from oxidative damage. Using two-dimensional electrophoresis, we investigated ceruloplasmin patterns in the CSF of human Parkinson's disease patients. Parkinson's disease ceruloplasmin profiles proved more acidic than those found in healthy controls and in other human neurological diseases (peripheral neuropathies, amyotrophic lateral sclerosis, and Alzheimer's disease); degrees of acidity correlated with patients' pathological grading. Applying an unsupervised pattern recognition procedure to the two-dimensional electrophoresis images, we identified representative pathological clusters. In vitro oxidation of CSF in two-dimensional electrophoresis generated a ceruloplasmin shift resembling that observed in Parkinson's disease and co-occurred with an increase in protein carbonylation. Likewise, increased protein carbonylation was observed in Parkinson's disease CSF, and the same modification was directly identified in these samples on ceruloplasmin. These results indicate that ceruloplasmin oxidation contributes to pattern modification in Parkinson's disease. From the functional point of view, ceruloplasmin oxidation caused a decrease in ferroxidase activity, which in turn promotes intracellular iron retention in neuronal cell lines as well as in primary neurons, which are more sensitive to iron accumulation. Accordingly, the presence of oxidized ceruloplasmin in Parkinson's disease CSF might be used as a marker for oxidative damage and might provide new insights into the underlying pathological mechanisms.

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“…Iron Influx/Efflux Studies-Astrocytes were purified from the brains of neonatal wild-type (Cp ϩ/ϩ ) and Cp-null mice (Cp Ϫ/Ϫ ) obtained from littermates and cultured as described previously (17). The Cp-null mice were generated in this laboratory as reported previously (6).…”

Section: Methodsmentioning

confidence: 99%

Glycosylphosphatidylinositol-anchored Ceruloplasmin Is Required for Iron Efflux from Cells in the Central Nervous System

Jeong

David

2003

Journal of Biological Chemistry

Self Cite

329

289

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Ceruloplasmin (Cp) is a ferroxidase that converts highly toxic ferrous iron to its non-toxic ferric form. A glycosylphosphatidylinositol (GPI)-anchored form of this enzyme is expressed by astrocytes in the mammalian central nervous system, whereas the secreted form is expressed by the liver and found in serum. Lack of this enzyme results in iron accumulation in the brain and neurodegeneration. Herein, we show using astrocytes purified from the central nervous system of Cpnull mice that GPI-Cp is essential for iron efflux and not involved in regulating iron influx. We also show that GPI-Cp colocalizes on the astrocyte cell surface with the divalent metal transporter IREG1 and is physically associated with IREG1. In addition, IREG1 alone is unable to efflux iron from astrocytes in the absence of GPI-Cp or secreted Cp. We also provide evidence that the divalent metal influx transporter DMT1 is expressed by astrocytes and is likely to mediate iron influx into these glial cells. The coordinated actions of GPI-Cp and IREG1 may be required for iron efflux from neural cells, and disruption of this balance could lead to iron accumulation in the central nervous system and neurodegeneration.

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Expression of a membrane‐bound form of the ferroxidase ceruloplasmin by leptomeningeal cells

Cited by 37 publications

References 43 publications

Atp7b −/− mice as a model for studies of Wilson's disease

Atp7b −/− mice as a model for studies of Wilson's disease

Ceruloplasmin Oxidation, a Feature of Parkinson's Disease CSF, Inhibits Ferroxidase Activity and Promotes Cellular Iron Retention

Glycosylphosphatidylinositol-anchored Ceruloplasmin Is Required for Iron Efflux from Cells in the Central Nervous System

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