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RESEARCH ON THE PATHOGENESIS AND PATHOPHYSIOLOGY OF HEREDITARY CERULOPLASMIN DEFICIENCY (ACERULOPLASMINEMIA)

Research Project

Project/Area Number 12670599
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionSHINSHU UNIVERSITY

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)

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)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2001: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2000: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsCERULOPLASMIN / GENE-TARGETING / IRON METABOLISM / OXIDATIVE STRESS / ASTROCYTE / フリーラジカル
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

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Yoshida K, Kaneko K, Miyajima H, Tokuda T, Nakamura A, Kato M, Ikeda S.: "Increased lipid peroxidation in the brains of aceruloplasminemia patients"Journal of Neurological Science. 175. 91-95 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kaneko K, Nakamura A, Yoshida K, Kametani F, Higuchi K, Ikeda S.: "Glial fibrillary acidic protein is greatly modified by oxidative stress in aceruloplasminemia brain"Free Radical Research. 36. 303-306 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kaneko K, Yoshida K, Arima K, Ohara S, Miyajima H, Kato T, Ohta M, Ikeda S.: "Astrocytic deformity and globular structures are characteristic of the brains of patients with aceruloplasminemia"Journal of Neuropathology and Experimental Neurology. 61. 1069-1077 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto K, Yoshida K, Miyagoe Y, Ishikawa A, Hanaoka K, Nomoto S, Kaneko K, Ikeda S, Takeda S.: "Quantitative evaluation of expression of iron-metabolism genes in ceruloplasmin-deficient mice"Biochimica et Biophysica Acta. 1588. 195-202 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 吉田邦広: "無セルロプラスミン血症"神経研究の進歩. 46. 859-867 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshida K, Kaneko K, Miyajima H, Tokuda T, Nakamura A, Kato M, Ikeda S.: "Increased lipid peroxidation in the brains of aceruloplasminemia Patients."J. Neurol. Sci.. 175. 91-95 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kaneko K, Nakamura A, Yoshida K, Kametani F, Higuchi K, Ikeda S.: "Glial fibrillary acidic protein is greatly modified by oxidative stress in aceruloplasminemia."Free Rad. Res.. 36. 303-306 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [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
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto K, Yoshida K, Miyagoe Y, Ishikawa A, Hanaoka K, Nomoto S, Kaneko K, Ikeda S, Takeda S.: "Quantitative Evaluation of Expression of Iron-Metabolism Genes in Ceruloplasmin-Deficient Mice."Biochimica Biophysica Acta. 1588. 195-202 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kaneko K, Yoshida K, Arima M, Ohara S, Miyajima H, Kato T, Ohta M, Ikeda S.: "Astrocytic deformity and globular structures are characteristic of the brains of patients with aceruloplasminemia"J. Neuropathol Exp. Neurol.. 61. 1069-1077 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yoshida K.: "Aceruloplasminemia. (in Japanese)"Shinkei Kenkyu No Shinpo. 46. 859-867 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kaneko K, Nakamura A, Yoshida K, Kametani F, Higuchi K, Ikeda S: "Glial fibrillary acidic protein is greatly modified by oxidative stress in aceruloplasminemia brain"Free Radical Research. 36. 303-306 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Loreal O, Turlin B, Pigeon C, Moisan A, Ropert M, Morice P, Gandon Y, Jouanolle A-M, Verin M, Hider RC, Yohida K, Brissot P: "Aceruloplasminemia : new clinical, pathological and therapeutic insights"Journal of Hepatology. 36. 851-856 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kaneko K, Yoshida K, Arima K, Ohara S, Miyajima H, Kato T, Ohta M, Ikeda S: "Astrocytic deformity and globular structures are characteristic of the brains of patients with aceruloplasminemia"Journal of Neuropathology and Experimental Neurology. 61. 1069-1077 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamamoto K, Yoshida K, Miyagoe Y, Ishikawa A, Hanaoka K, Nomoto S, Kaneko K, Ikeda S, Takeda S: "Quantitative evaluation of expression of iron-metabolism genes in ceruloplasmin-deficient mice"Biochimica et Biophysica Acta. 1588. 195-202 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 吉田邦広: "無セルロプラスミン血症"神経研究の進歩. 46. 859-867 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kaneko K, Nakamura A, Yoshida K, et al.: "Glial fibrillary acidic protein is greatly modified by oxidative stress in aceruloplasminemia brain"Free Radical Research. (in press).

    • Related Report
      2001 Annual Research Report
  • [Publications] Yoshida K,Kaneko K,Miyajima H, er al.: "Increased lipid peroxidation in the brains of aceruloplasminemia patients"Journal of Neurological Science. 175. 91-95 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 吉田邦広: "無セルロプラスミン血症-鉄の細胞内過剰沈着と酸化的ストレス-"信州医学雑誌. 47. 103-112 (1999)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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