Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson's disease

Boll, Marie‐Catherine; Sotelo, Julio; Otero, E.; Alcaraz-Zubeldia, Mireya; Rı́os, Camilo

doi:10.1016/s0304-3940(99)00221-9

Cited by 86 publications

(53 citation statements)

References 18 publications

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“…The functionality reduction that follows Cp oxidation correlates with a Cp electrophoretic pattern similar to that observed in CSF of PD. Given that CSF ferroxidase activity is substantially due to Cp (Madsen and Gitlin, 2007), it is reasonable to associate the Cp oxidative modifications found in PD patients with the reported reduction in CSF ferroxidase activity (Boll et al, 1999(Boll et al, , 2008. Furthermore, oxidative modification in Cp leads to copper release (Kang et al, 2001; this study), a finding that possibly explains why copper increases in the CSF of both PD and AD patients (Boll et al, 2008;Brewer et al, 2010).…”

Section: Discussionmentioning

confidence: 54%

“…In PD, imbalances between the generation of oxidant products and ROS scavenging systems, together with improper iron metabolism, contribute to neurological damage . Reduced CSF ferroxidase activity (Boll et al, 1999(Boll et al, , 2008, increased oxidative stress in CNS, and iron overload in SN (Götz et al, 2004) are PD features that potentially connect to the Cp oxidation here observed. The functionality reduction that follows Cp oxidation correlates with a Cp electrophoretic pattern similar to that observed in CSF of PD.…”

Section: Discussionmentioning

confidence: 57%

“…The literature reports a reduced level of ferroxidase activity in PD CSF (Boll et al, 1999(Boll et al, , 2008, and it is noteworthy that CSF fer- Figure 2. Cp pattern acidification discriminates healthy subjects and correlates with Parkinson's disease grading.…”

Section: Oxidation Decreases Cp Ferroxidase Activitymentioning

confidence: 99%

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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.

120

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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Section: Discussionmentioning

confidence: 54%

Section: Discussionmentioning

confidence: 57%

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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.

120

114

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“…First, it has been suggested that changes in trace metal concentrations in the brain may be related to the long-term toxicity of L-DOPA (Weiner et al, 1978). Second, a clinical study (Boll et al, 1999) demonstrated that L-DOPA can significantly affect brain ceruloplasmin, a major factor in the regulation of regional brain iron content and that cerebrospinal fluid ferroxidase (CP) in L-DOPA-treated patients with PD was significantly higher than that in patients with PD who were not This work was supported by research grants from the National Key Laboratory of Chinese Medicine and Molecular Pharmacology, The Hong Kong Polytechnic University (G-YX14, ASD-A256, G-YD78, A-PD92, G-T616, and G-T856), Nanton University, and Competitive Earmarked grants from The Hong Kong Research Grants Council (PolyU5270/01M/B-Q445).Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org. doi:10.1124/mol.105.017756.…”

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confidence: 99%

Increased Divalent Metal Transporter 1 Expression Might Be Associated with the Neurotoxicity of l-DOPA

Chang¹,

Ke²,

Du³

et al. 2005

Mol Pharmacol

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Based on the available data, we speculated that changes in brain iron metabolism induced by L-DOPA might be associated with the neurotoxicity of L-DOPA. To investigate this possibility, the effects of L-DOPA on the expression of iron influx proteins [transferrin receptor (TfR) and divalent metal transporter 1 (DMT1)], iron efflux protein (ferroportin 1), and iron uptake in C6 glioma cells were determined in this study using Northern blot and Western blot analysis and the calcein method. The findings showed that treatment of C6 cells with different concentrations of L-DOPA (0 -100 M) did not affect the expression of mRNA and protein of TfR and DMT1 with iron-responsive element (ϩIRE) and protein of ferroportin 1. However, a significant increase in the expression of DMT1(ϪIRE) mRNA and protein was found in cells treated, respectively, with 10 and 30 M L-DOPA (mRNA) and 1, 5, 10 and 30 M L-DOPA (protein). The increase in DMT(ϪIRE) protein induced by L-DOPA treatment was in parallel with the increase in DMT(ϪIRE) mRNA. The levels of DMT1(ϪIRE) mRNA and protein peaked in the cells treated with 10 M L-DOPA and then decreased progressively with increasing concentrations of L-DOPA. Further study demonstrated that treatment of the cells with 10 M L-DOPA induced a significant increase in ferrous uptake by C6 glioma cells. The findings suggested that the increased DMT1(ϪIRE) expression might be partly associated with the neurotoxicity of L-DOPA. Clinical relevance of the findings needs to be investigated further.Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized mainly by degeneration of dopamine-containing neurons. The affected sections of the brain are therefore deprived of adequate amounts of the neurotransmitter dopamine (Foley, 2000). Because dopamine itself cannot access the brain directly, its natural precursor, L-DOPA, is used in clinical treatment of patients with PD. L-DOPA remains the most effective treatment for the symptomatic control of PD (Dunnett and Björklund, 1999;LeWitt and Nyholm, 2004). However, it was reported that long-term administration of high oral doses could cause drug-induced involuntary movements, on-off fluctuation of efficacy, and dyskinesias (Jenner and Brin, 1998;Foster and Hoffer, 2004).The causes of the long-term side effects caused by L-DOPA treatment of PD are not yet completely known. Based on available data, we speculated that changes in brain iron metabolism induced by L-DOPA might be associated with neurotoxicity or side effects of L-DOPA. First, it has been suggested that changes in trace metal concentrations in the brain may be related to the long-term toxicity of L-DOPA (Weiner et al., 1978). Second, a clinical study (Boll et al., 1999) demonstrated that L-DOPA can significantly affect brain ceruloplasmin, a major factor in the regulation of regional brain iron content and that cerebrospinal fluid ferroxidase (CP) in L-DOPA-treated patients with PD was significantly higher than that in patients with PD who were not This work was supported ...

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“…Another study investigating oxidative stress in PD, AD, ALS and Huntington's disease (HD) found decreased Cu/Zn-dependent superoxide dismutase (SOD1) activity in all these diseases (Boll et al, 2008); also, an increase of modified forms of Cu/Zn-dependent SOD has been published (Guo et al, 2009). Other studies found reduced CSF concentration of ceruloplasmin and ferroxidase activity, the enzyme that catalyzes the conversion of Fe 2+ in Fe 3 (Boll et al, 1999;Boll et al, 2008;Abdi et al 2006), whereas CSF transferrin levels where unchanged in PD (Loeffler et al, 1994;van Kamp et al, 1995).…”

Section: Other Oxidative Stress Related Proteinsmentioning

confidence: 91%

CFS Biomarkers in Parkinson’s Disease

Parnetti¹,

Castrioto²,

Carlo³

et al. 2011

Diagnosis and Treatment of Parkinson's Disease

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Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson's disease

Cited by 86 publications

References 18 publications

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

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

Increased Divalent Metal Transporter 1 Expression Might Be Associated with the Neurotoxicity of l-DOPA

CFS Biomarkers in Parkinson’s Disease

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