2002 Fiscal Year Final Research Report Summary
RESEARCH ON THE PATHOGENESIS AND PATHOPHYSIOLOGY OF HEREDITARY CERULOPLASMIN DEFICIENCY (ACERULOPLASMINEMIA)
| Project/Area Number |
12670599
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | SHINSHU UNIVERSITY |
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Principal Investigator |
YOSHIDA Kunihiro SHINSHU UNIVERSITY HOSPITAL, DIVISION OF CLINICAL AND MOLECULAR GENETICS, ASSOCIATE PROFESSOR, 医学部附属病院・遺伝子診療部・副部長助教授 (90242693)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEDA Shin'ichi NATIONAL INSTITUTE OF NEUROSCIENCE, NATIONAL CENTER OF NEUROLOGY AND PSYCHIATRY, DEPARTMENT OF MOLECULAR THERAPY, DIRECTOR OF THE DEPARTMENT, 神経研究所・遺伝子疾患治療研究部, 部長 (90171644)
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| Project Period (FY) |
2000 – 2002
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| Keywords | CERULOPLASMIN / GENE-TARGETING / IRON METABOLISM / OXIDATIVE STRESS / ASTROCYTE |
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| Research Abstract |
Aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by mutations in the ceruloplasmin (CP) gene. We scrutinized the brains of 5 patients with this disease histopathologically and immunohistochemically. In the brain, the basal ganglia (especially the caudate nucleus and putamen) were most severely affected, where heavy iron deposition and extensive loss of neurons were observed. Iron overload was more prominent in astrocytes than in neurons. Markedly deformed astrocytes and spheroid-like globular structures were seen in proportion to the degree of iron deposition. Globular structures clearly reacted with anti-glial fibrillary acidic protein and anti-S-100 antibodies, but not with antibodies for neuronal marker proteins, such as neurofilament and synaptophysin. Therefore, they presumably originated from astrocytes. Deformed astrocytes and globular structures also reacted positively to anti-4-hydroxynonenal antibody. These findings indicate that morphological c
… More
hanges of astrocytes are closely linked to iron overload and subsequent oxidative stress.
In order to elucidate the functional involvement of CP in iron metabolism, we generated CP-deficient (CP^<-/->) mice. The mice showed a marked iron overload in the liver and mild microcytic and hypochromic anemia, but they did not exhibit iron overload in any other organs including the brain. We examined expression levels of the iron-metabolism genes in the duodenum and liver with TaqMan RT-PCR. The divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), and hephaestin (HEPH) genes were not up-regulated in the duodenum from CP^<-/-> mice. This result is compatible with a previous ferrokinetic study by Harris et al., which showed no difference in the rate of intestinal iron absorption between CP^<-/-> and CP^<+/+> mice. Together with the fact that sex-linked anemia (sla) mice, which carry a mutation in the HEPH gene, show defective iron absorption in the duodenum and severe iron deficiency anemia, our data suggest that CP is less important than HEPH for intestinal iron absorption. In the liver, CP^<-/-> mice showed no increase of gene expression for DMT1 and transferrin receptors (TFR and TFR2), suggesting that any known pathway of iron uptake is not activated in hepatocytes in CP^<-/-> mice. This result supports the hypothesis that CP mainly acts to release iron from cells in the liver. Less
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[Publications] Loreal O, Turlin B, Pigeon C, Moisan A, Ropert M, Morice P, Gandon Y, Jouanolle A-M, Verin M, Hider RC, Yoshida K, Brissot P.: "Aceruloplasminemia : new clinical, pathological and therapeutic insights"Journal of Hepatology. 36. 851-856 (2002)
Description
「研究成果報告書概要(和文)」より
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[Publications] Loreal O, Turlin B, Pigeon C, Moisan A, Ropert M, Morice P, Gandon Y, Jouanolle A-M, Verin M, Hider RC, Yoshida K, Brissot P.: "Aceruloplasminemia: new clinical, pathophysiological and therapeutic insights."J Hepatol. 36. 851-856 (2002)
Description
「研究成果報告書概要(欧文)」より
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