title: Functional relevance of ceruloplasmin mutations in Parkinson's disease.
abstract: Increased iron levels of the substantia nigra and the discovery of ceruloplasmin mutations in patients with Parkinson's disease (PD) imply impaired iron metabolism in this neurodegenerative disorder. Ceruloplasmin has ferroxidase activity oxidizing iron(II) to iron(III). In the present study, we analyzed the amount of ceruloplasmin, iron, ferritin, and transferrin and the ceruloplasmin ferroxidase activity in serum of patients with the diagnosis of PD carrying the ceruloplasmin mutations I63T, D544E, and R793H. The impact of these missense mutations on the biosynthesis of holo-ceruloplasmin was investigated in cell culture experiments. Functional relevance was found for the ceruloplasmin mutations I63T and D544E. In vivo, the I63T mutation resulted in half the normal ceruloplasmin concentration and markedly reduced ferroxidase activity in serum from a heteroallelic PD patient. In cell culture, the I63T glycosylphosphatidylinositol (GPI)-linked ceruloplasmin isoform was retained in the endoplasmatic reticulum of human embryonic kidney cells. Furthermore, the D544E polymorphism resulted in significantly reduced serum ceruloplasmin levels and ferroxidase activity in heteroallelic patients and in expression of mainly apo-ceruloplasmin in cell culture. Our studies indicate that altered activity of ceruloplasmin may present a vulnerability factor for iron induced oxidative stress in PD.
authors.affiliation: Department of Medical Genetics, University of Tuebingen, Tuebingen,Germany. helmine.hochstrasser@med.uni-tuebingen.de
authors.forename: Helmine
authors.initials: H
authors.lastname: Hochstrasser
authors.forename: Jürgen
authors.initials: J
authors.lastname: Tomiuk
authors.forename: Uwe
authors.initials: U
authors.lastname: Walter
authors.forename: Stefanie
authors.initials: S
authors.lastname: Behnke
authors.forename: Jörg
authors.initials: J
authors.lastname: Spiegel
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
authors.forename: Georg
authors.initials: G
authors.lastname: Becker
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Daniela
authors.initials: D
authors.lastname: Berg
mesh_terms: D000483:Alleles; D002460:Cell Line; D002570:Ceruloplasmin / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D005293:Ferritins / Q000737:chemistry; D019084:Fluorescent Antibody Technique, Indirect; D006031:Glycosylation; D017261:Glycosylphosphatidylinositols / Q000737:chemistry; D006579:Heterozygote; D006801:Humans; D047468:Immunoprecipitation; D007501:Iron / Q000737:chemistry / Q000378:metabolism*; D007668:Kidney / Q000473:pathology; D008856:Microscopy, Fluorescence; D009154:Mutation; D020125:Mutation, Missense; D019636:Neurodegenerative Diseases / Q000473:pathology; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D011489:Protein Denaturation; D017510:Protein Folding; D020033:Protein Isoforms; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D014168:Transferrin / Q000737:chemistry
chemical_list: D017261:Glycosylphosphatidylinositols; D020033:Protein Isoforms; D014168:Transferrin; D005293:Ferritins; D007501:Iron; D002570:Ceruloplasmin