Ceruloplasmin oxidation, a feature of Parkinson's disease CSF, inhibits ferroxidase activity and promotes cellular iron retention
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A contributing factor to the increased iron accumulation in Parkinson's disease might be increased DMT1 activity or decreased ferroxidase activity of ceruloplasmin, both of which would increase total intracellular iron.
“A contributing factor to the increased iron accumulation in Parkinson’s disease might be increased DMT1 activity or decreased ferroxidase activity of ceruloplasmin, both of which would increase total intracellular iron, as reported in an animal model of Parkinson’s disease109 and in patients.131–134”
From The role of iron in brain ageing and neurodegenerative disorders (2014) · cites this paper as [134]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915 · see citing works
Parkinsonism: onset, progression, and mortality
Hoehn, M. M., & Yahr, M. D. (1967) · Neurology · doi:10.1212/wnl.17.5.427 · Cited by 12,107 · cited 2× · see citing works
“Interestingly, PD patients’ clinical status (as UPDRS score, Table 1) and Cp acidification (signal in region A as percentage of total WB Cp signal) were found to correlate (Pearson’s correlation coefficient r 0.745; p 0.0022) (Fig.”
MethodInfluentialBrooks, B. R. (1994) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(94)90191-0 · Cited by 2,144 · see citing works
Molecular Pathways of Neurodegeneration in Parkinson's Disease
Dawson, T. M., & Dawson, V. L. (2003) · Science · doi:10.1126/science.1087753 · Cited by 1,659 · see citing works
Pathogenesis of parkinson's disease: dopamine, vesicles and α-synuclein
Lotharius, J., & Brundin, P. (2002) · Nature reviews. Neuroscience · doi:10.1038/nrn983 · Cited by 1,283 · see citing works
Protein carbonylation in human diseases
Dalle-Donne, I., Giustarini, D., Colombo, R., Rossi, R., & Milzani, A. (2003) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(03)00031-5 · Cited by 961 · see citing works
C ERULOPLASMIN M ETABOLISM AND F UNCTION
Hellman, N. E., & Gitlin, J. D. (2002) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.22.012502.114457 · Cited by 930 · see citing works
The diagnosis of Parkinson’s disease
Tolosa, E., Wenning, G., & Poewe, W. (2006) · The Lancet Neurology · doi:10.1016/s1474-4422(05)70285-4 · Cited by 902 · see citing works
Duce, J. A., Tsatsanis, A., Cater, M. A., James, S., Robb, E. L., Wikhe, K., Leong, S. L., Perez, K. A., Johanssen, T., Greenough, M. A., et al. (2010) · Cell · doi:10.1016/j.cell.2010.08.014 · Cited by 682 · see citing works
Copper and iron disorders of the brain
Madsen, E., & Gitlin, J. D. (2007) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.30.051606.094232 · Cited by 557 · see citing works
Clinical limits of amyotrophic lateral sclerosis.
Mulder, D. W. (1982) · PubMed · Cited by 444 · see citing works
Iron trafficking inside the brain
Moos, T., Nielsen, T. R., Skjørringe, T., & Morgan, E. H. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04976.x · Cited by 421 · see citing works
Ceruloplasmin regulates iron levels in the CNS and prevents free radical injury
Patel, B. N., Dunn, R. J., Jeong, S. Y., Zhu, Q., Julien, J.-P., & David, S. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-15-06578.2002 · Cited by 379 · see citing works
Jeong, S. Y., & David, S. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301988200 · Cited by 377 · see citing works
De Domenico, I., Ward, D. M., di Patti, M. C. B., Jeong, S. Y., David, S., Musci, G., & Kaplan, J. (2007) · The EMBO Journal · doi:10.1038/sj.emboj.7601735 · Cited by 350 · see citing works
The Relevance of Iron in the Pathogenesis of Parkinson's Disease
Götz, M. E., Double, K. L., Gerlach, M., Youdim, M. B. H., & RIEDERERE, P. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1306.017 · Cited by 342 · see citing works
Individual dopaminergic neurons show raised iron levels in Parkinson disease
Oakley, A. E., Collingwood, J. F., Dobson, J., Love, G., Perrott, H. R., Edwardson, J. A., Elstner, M., & Morris, C. M. (2007) · Neurology · doi:10.1212/01.wnl.0000262033.01945.9a · Cited by 273 · see citing works
Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis
Harris, Z. L., Klomp, L. W. J., & Gitlin, J. (1998) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/67.5.972s · Cited by 253 · see citing works
YOUDIM, M. B. H., STEPHENSON, G., & SHACHAR, D. B. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1306.025 · Cited by 233 · cited 1× · see citing works
“In PD, imbalances between the generation of oxidant products and ROS scavenging systems, together with improper iron metabolism, contribute to neurological damage (Youdim et al., 2004).”
BackgroundCarrı̀, M. T., Ferri, A., Cozzolino, M., Calabrese, L., & Rotilio, G. (2003) · Brain Research Bulletin · doi:10.1016/s0361-9230(03)00179-5 · Cited by 209 · see citing works
Microarrays for an Integrative Genomics
Kohane, I. S., Kho, A. T., & Butte, A. J. (2002) · The MIT Press eBooks · doi:10.7551/mitpress/4594.001.0001 · Cited by 175 · see citing works
Boll, M.-C., Alcaraz-Zubeldia, M., Montes, S., & Rios, C. (2008) · Neurochemical Research · doi:10.1007/s11064-008-9610-3 · Cited by 173 · see citing works
Ceruloplasmin in neurodegenerative diseases
Vassiliev, V. B., Harris, Z. L., & Zatta, P. F. (2005) · Brain Research Reviews · doi:10.1016/j.brainresrev.2005.03.003 · Cited by 148 · see citing works
Jin, L., Wang, J., Zhao, L., Jin, H., Fei, G., Zhang, Y., Zeng, M., & Zhong, C. (2010) · Brain · doi:10.1093/brain/awq319 · Cited by 129 · see citing works
The Etiopathogenesis of Parkinson Disease and Suggestions for Future Research. Part I
Litvan, I., Halliday, G. M., Hallett, M., Goetz, C. G., Rocca, W. A., Duyckaerts, C. J., Ben‐Shlomo, Y., Dickson, D. W., Lang, A. E., Chesselet, M., et al. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3180415e42 · Cited by 122 · see citing works
Pelizzoni, I., Macco, R., Morini, M. F., Zacchetti, D., Grohovaz, F., & Codazzi, F. (2010) · Aging Cell · doi:10.1111/j.1474-9726.2010.00652.x · Cited by 110 · see citing works
Self-citationGrimm, S., Höhn, A., Davies, K. J. A., & Grune, T. (2010) · Free Radical Research · doi:10.3109/10715762.2010.512040 · Cited by 108 · see citing works
Copper and Ceruloplasmin Abnormalities in Alzheimer’s Disease
Brewer, G. J., Kanzer, S. H., Zimmerman, E. A., Celmins, D. F., Heckman, S. M., & Dick, R. (2010) · American Journal of Alzheimer s Disease & Other Dementias® · doi:10.1177/1533317510375083 · Cited by 104 · see citing works
Ceruloplasmin Protects Injured Spinal Cord from Iron-Mediated Oxidative Damage
Rathore, K. I., Kerr, B., Redensek, A., López-Vales, R., Jeong, S. Y., Ponka, P., & David, S. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3649-08.2008 · Cited by 97 · see citing works
Reduced ferroxidase activity in the cerebrospinal fluid from patients with Parkinson's disease
Boll, M.-C., Sotelo, J., Otero, E., Alcaraz-Zubeldia, M., & Rios, C. (1999) · Neuroscience Letters · doi:10.1016/s0304-3940(99)00221-9 · Cited by 92 · see citing works
Age-related changes in human ceruloplasmin. Evidence for oxidative modifications
Musci, G., di Patti, M. C. B., Fagiolo, U., & Calabrese, L. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)38663-6 · Cited by 85 · see citing works
Ceruoplasmin Is Increased in Cerebrospinal Fluid in Alzheimerʼs Disease but Not Parkinsonʼs Disease
Loeffler, D. A., DeMaggio, A. J., Juneau, P. L., Brickman, C. M., Mashour, G. A., Finkelman, J., Pomara, N., & LeWitt, P. A. (1994) · Alzheimer Disease & Associated Disorders · doi:10.1097/00002093-199408030-00005 · Cited by 78 · see citing works
Oxidative stress and cell death in cells expressing L-ferritin variants causing neuroferritinopathy
Cozzi, A., Rovelli, E., Frizzale, G., Campanella, A., Amendola, M., Arosio, P., & Levi, S. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.09.009 · Cited by 78 · see citing works
Self-citationCannistraci, C. V., Ravasi, T., Montevecchi, F. M., Ideker, T. E., & Alessio, M. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btq376 · Cited by 75 · see citing works
Self-citationCannistraci, C. V., Montevecchi, F. M., & Alessio, M. (2009) · PROTEOMICS · doi:10.1002/pmic.200800538 · Cited by 74 · see citing works
Self-citationCeruloplasmin in neurodegenerative diseases
Texel, S. J., Xu, X., & Harris, Z. L. (2008) · Biochemical Society Transactions · doi:10.1042/bst0361277 · Cited by 73 · see citing works
M�ller, T., Hefter, H., Hueber, R., et al. (2004) · Journal of Neurology · doi:10.1007/s00415-004-1610-x · Cited by 65 · see citing works
Lower serum ceruloplasmin levels correlate with younger age of onset in Parkinson’s disease
Bharucha, K. J., Friedman, J. H., Vincent, A. S., & Ross, E. D. (2008) · Journal of Neurology · doi:10.1007/s00415-009-0063-7 · Cited by 62 · see citing works
Codazzi, F., Cesare, A. D., Chiulli, N., Albanese, A., Meyer, T., Zacchetti, D., & Grohovaz, F. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0478-06.2006 · Cited by 60 · see citing works
Self-citationFahn, S. (1987) · Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques · doi:10.1017/s0317167100038051 · Cited by 58 · see citing works
Oxidative modification of human ceruloplasmin by peroxyl radicals
Kang, J. H., Kim, K. S., Choi, S. Y., Kwon, H. Y., & Won, M. H. (2001) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/s0304-4165(01)00198-2 · Cited by 54 · see citing works
Tapryal, N., Mukhopadhyay, C., Das, D., Fox, P. L., & Mukhopadhyay, C. K. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m804079200 · Cited by 54 · see citing works
Kang, J. H., Kim, K. S., Choi, S. Y., et al. (2002) · Molecules and Cells · doi:10.1016/s1016-8478(23)15065-5 · Cited by 51 · see citing works
Fragmentation of human ceruloplasmin induced by hydrogen peroxide
Choi, S.-W. (2000) · Biochimie · doi:10.1016/s0300-9084(00)00380-1 · Cited by 47 · see citing works
Expression of a membrane‐bound form of the ferroxidase ceruloplasmin by leptomeningeal cells
Mittal, B., Doroudchi, M. M., Jeong, S. Y., Patel, B. N., & David, S. (2003) · Glia · doi:10.1002/glia.10158 · Cited by 46 · see citing works
The Etiopathogenesis of Parkinson Disease and Suggestions for Future Research. Part II
Litvan, I., Chesselet, M., Gasser, T., Monte, D. A. D., Parker, D., Hagg, T., Hardy, J., Jenner, P. G., Myers, R. H., Price, D. D., et al. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318053716a · Cited by 45 · see citing works
Ceruloplasmin and superoxide dismutase (SOD1) in Parkinson's disease: A follow-up study
Tórsdóttir, G., Sveinbjörnsdóttir, S., Kristinsson, J., Snædal, J., & Jøhannesson, T. (2005) · Journal of the Neurological Sciences · doi:10.1016/j.jns.2005.10.015 · Cited by 38 · see citing works
Pigment epithelium‐derived factor is differentially expressed in peripheral neuropathies
Conti, A., Ricchiuto, P., Iannaccone, S., et al. (2005) · PROTEOMICS · doi:10.1002/pmic.200402088 · Cited by 35 · see citing works
Self-citationConti, A., Iannaccone, S., Sferrazza, B., Monte, L. B. D., Cappa, S. F., Franciotta, D. M., Olivieri, S., & Alessio, M. (2008) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.200780081 · Cited by 33 · see citing works
Self-citationBettegazzi, B., Mihailovich, M., Cesare, A. D., Consonni, A., Macco, R., Pelizzoni, I., Codazzi, F., Grohovaz, F., & Zacchetti, D. (2010) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2010.07482.x · Cited by 30 · see citing works
Self-citationMerle, U., Tuma, S., Herrmann, T. R. W., Muntean, V., Volkmann, M., Gehrke, S. G., & Stremmel, W. (2009) · Journal of Gastroenterology and Hepatology · doi:10.1111/j.1440-1746.2009.06173.x · Cited by 26 · see citing works
Ruggeri, G., Santambrogio, P., Bonfiglio, F., Levi, S., Bugari, G., Verardi, R., Cazzola, M., Invernizzi, R., Zambell, L. M., Albertini, A., et al. (1992) · British Journal of Haematology · doi:10.1111/j.1365-2141.1992.tb08183.x · Cited by 13 · see citing works
Blandini, F., Mangiagalli, A., Martignoni, E., et al. (2003) · Neurological Sciences · doi:10.1007/s10072-003-0107-1 · Cited by 10 · see citing works
Baraj, B., Cortina, J. L., Sastre, A. M., et al. (1998) · Fresenius Journal of Analytical Chemistry · doi:10.1007/s002160050687 · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Free Radicals: Properties, Sources, Targets, and Their Implication in Various Diseases
Phaniendra, A., Jestadi, D. B., & Periyasamy, L. (2015) · Indian Journal of Clinical Biochemistry · doi:10.1007/s12291-014-0446-0 · Cited by 2,886 · see citing works
The role of iron in brain ageing and neurodegenerative disorders
Ward, R. J., Zucca, F. A., Duyn, J. H., Crichton, R. R., & Zecca, L. (2014) · The Lancet Neurology · doi:10.1016/s1474-4422(14)70117-6 · Cited by 1,819 · see citing works
Interactions of iron, dopamine and neuromelanin pathways in brain aging and Parkinson's disease
Zucca, F. A., Segura-Aguilar, J., Ferrari, E., Muñoz, P., Paris, I., Sulzer, D., Sarna, T., Casella, L., & Zecca, L. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2015.09.012 · Cited by 659 · see citing works
Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease
Ayton, S., Lei, P., Duce, J. A., Wong, B. X. W., Sedjahtera, A., Adlard, P. A., Bush, A. I., & Finkelstein, D. I. (2013) · Annals of Neurology · doi:10.1002/ana.23817 · Cited by 264 · see citing works
Iannaccone, S., Cerami, C., Alessio, M., Garibotto, V., Panzacchi, A., Olivieri, S., Gelsomino, G., Moresco, R. M., & Perani, D. (2013) · Parkinsonism & Related Disorders · doi:10.1016/j.parkreldis.2012.07.002 · Cited by 221 · see citing works
Self-citationMetallobiology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity
Hare, D. J., Adlard, P. A., Doble, P. A., & Finkelstein, D. I. (2013) · Metallomics · doi:10.1039/c2mt20164j · Cited by 78 · see citing works
- Authors
- Olivieri, S., Conti, A., Iannaccone, S., Cannistraci, C. V., Campanella, A., Barbariga, M., Codazzi, F., Pelizzoni, I., Magnani, G., Pesca, M., Franciotta, D., Cappa, S. F., & Alessio, M.
- Affiliations
- IRCCS Ospedale San Raffaele (IT)
- Vita-Salute San Raffaele University (IT)
- King Abdullah University of Science and Technology (SA)
- University of Salerno (IT)
- Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-12-14
- Volume
- 31
- Issue
- 50
- Pages
- 18568-18577
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6623910
- OpenAlex
- W1998198134
- Cited by
- 125
- References
- 54
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 7 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 8 · 2019: 11 · 2018: 11 · 2017: 12 · 2016: 10 · 2015: 11 · 2014: 17 · 2013: 9 · 2012: 4
- FWCI
- 6.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Keywords
- Parkinson's disease, ceruloplasmin, protein oxidation, cerebrospinal fluid, ferroxidase activity, iron retention, oxidative stress, protein carbonylation, iron accumulation, oxidative damage markers
- MeSH terms
- Aged, Aged, 80 and over, Animals, Astrocytes, Cells, Cultured, Ceruloplasmin, Female, Humans, Iron, Male, Middle Aged, Neurons, Oxidation-Reduction, Parkinson Disease, Rats, Sprague-Dawley, Oxidative Stress, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
