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Induction Mechanism of Apoptosis in Cerebrotendinous Xanthomatosis

Research Project

Project/Area Number 13480201
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionOchanomizu University

Principal Investigator

SEYAMA Yousuke  Ochanomizu University, Faculty of Human Life and Environmental Sciences, Professor, 生活科学部, 教授 (90010082)

Co-Investigator(Kenkyū-buntansha) SAWADA Rumi  Ochariomizu University, Faculty of Human Life and Environmental Sciences, Assistant Professor, 生活科学部, 助手 (30345409)
FUJIKAWA Yoko  Ochanomizu University, Faculty of Human Life and Environmental Sciences, Associate Professor, 生活科学部, 助教授 (50293105)
KUBOTA Shunichiro  The University of Tokyo, Graduate School of Arts and Sciences, Professor, 生活科学部, 教授 (00260480)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥13,400,000 (Direct Cost: ¥13,400,000)
Fiscal Year 2002: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2001: ¥10,200,000 (Direct Cost: ¥10,200,000)
Keywordscerebrotendinous xanthomatosis / CTX / Purkinje cell / cholestanol / apoptosis / cerebellar symptom
Research Abstract

Onset of CTX is usually in early teens and mental retardation is most frequently observed at this stage. Pyramidal sign and progressive cerebellar symptom appear at puberty together with atactic gait, lateral nystagmus or atactic dysphasia. Juvenile cataract also appears in late teens. Most characteristic symptom is xanthoma in brain, tendon, muscle and lung. Treatment is symptomatic therapy, and oral administration of chenodeoxycholic acid is effective to reduce the size of xan-thoma. By feeding experiments, we proved that the high concentration of cholestanol induced the accumulation of chole-stanol in cerebellum and caused the neurological disturbance. We formulated a hypothesis that cholestanol in serum of CTX patients might induce neuronal cell death in cerebellum and eventually cerebellar ataxia would occur. In the present study, we developed hypercholestanolemia rats and examined the effects of cholestanol on death of cerebellar neuronal cells, corneal endothelial and lens epith … More elial cells. Apoptosis was evident in cells cultured with cholestanol in these cells. As activities of interleukin-1β-converting enzyme (ICE) and CPP32 protease were increased in cells cultured with cholestanol, all these data taken together suggest that cholestanol induced apoptosis. Our observation may explain the mechanism of cerebellar ataxia, cataract and corneal opacities of CTX patients. We studied a 44-year old woman with progressive frontal lobe dementia and spastic araplegia. Examination revealed increased serum levels of cholestanol and heterozygous mutation of the sterol 27-hydroxylase gene (CYP27), In genomic DNA, both the G and A were found at codon 441, indicating the heterozygous pattern of the mutation of CGG441Arg to CAG441Gln. Computed tomography and magnetic resonance imaging (MRI) of the brain showed cerebral atrophy, which was marked in the frontal area. Cerebral MR images showed diffuse symmetric areas of hyperintensity in the white matter of the lateral ventricles in the optic radiation. Less

Report

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

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Rystedt E, Olin M, Seyama Y, Buchmann M, et al.: "Cerebrotendinous xanthomatosis : molecular characterization of two Scandinavian sisters"J Intern Med. 252. 259-264 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomioka M, Sameshima M, Nakano H, Kubo T, et al.: "A possible intermediate step during apoptotic execution"Hum Cell. 15. 43-51 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nemoto T, Hori H, Yoshimoto M, Seyama Y, Kubota S: "Overexpression of omithine decarboxylase enhances endothelial proliferation by suppressing endostatin expression"Blood. 99(4). 1478-1481 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomioka M, Shirotani K, Iwata N, Lee HJ, Yang F, et al.: "In vivo role of caspases in excitotoxic neuronal death : generation and analysis of transgenic mice expressing baculoviral caspase inhibitor"Brain Res Mol Brain Res. 108. 18-32 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishibashi Y, Ito H, Seyama Y, Kubota S: "Anti-alpha2 integrin antibody induces secretion and activation of 72-kDa Progelatinase by human fibroblasts"IUBMB Life. 51. 25-31 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sugama S, Kimura A, Chen W, Kubota S, Seyama Y, et al.: "Frontal lobe dementia with abnormal cholesterol metabolism and heterozygous mutation in sterol 27-hydroxylas gene (CYP 27)"J Inherit Metab Dis. 24. 379-392 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Rystedt E, Olin M, Seyama Y, Buchmann M, Berstad A, Eggertsen G Bjorkhem I: "Cerebrotendinous xanthomatosis : molecular characterization of two Scandinavian sisters"J Intern Med. 252. 259-264 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomioka M, Sameshima M, Nakano H,Kubo T, Shinohara K, Seyama Y, Kawashima S, Tones S: "A possible intermediate step during apoptotic execution"Hum Cell.. 15. 43-51 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nemoto T, Hori H, Yoshimoto M, Seyama Y, Kubota S: "Overexpression of omithine decarboxylase enhances endothelial proliferation by suppressing endostatin expression"Blood. 99. 1478-1481 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tomioka M, Shirotani K, Iwata N, Lee HJ, Yang F, Cole GM, Seyama Y, Saido TC: "In vivo role of caspases in excitotoxic neuronal death:generation and analysis of transgenic mice expressing baculoviral caspase inhibitor, p35, in postnatal neurons"Brain Res Mol Brain Res. 108. 18-32 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishibashi Y, Ito H, Seyama Y, Kubota S.: "Anti-alpha2 integrin antibody induces secretion and activation of 72-kDa progelatinase by human fibroblasts"IUBMB Life. 51. 25-31 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sugama, S., Kimura, A., Chen, W., Kubota, S., Seyama, Y, Taira, N., Eto, Y: "Frontal lobe dementia with abnormal cholesterol metabolism and heterozygous mutation in sterol 27-hydroxylase gene (CYP 27)"J Inherit Metab Dis. 24. 379-392 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nemoto T, Hori H, Yoshimoto M, Seyama Y, Kubota S: "Overexpression of ornithine decarboxylase enhances endothelial proliferation by suppressing endostatin expession"Blood. 99(4). 1478-1481 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Sugama S, Kimura A, Chen W, Kubota S, Seyama Y, Taira N, Eto Y.: "Frontal lobe dementia with abnormal cholesterol metabolism and heterozygous mutation in sterol 27-hydroxylase gene (CYP27)"Journal of Inherited Metabolic Disease. 24(3). 379-392 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 井上賢治, 久保田俊一郎, 脊山洋右: "脳腱黄色腫症"日本臨床. 59(3). 348-352 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Togo M, Toda T, Nguyen LA, Kubota S, Tsukamoto K, et al.: "Genetic analysis of phytosterolaemia"Journal of Inherited Metabolic Disease. 24(1). 43-50 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Cui Y, Otsuka M, Fujiwara, Y.: "Reduction of dehydroerythorbic acid in vitamin C-deficient guinea pigs"J. Nutr. Sci, Vitaminol. 47. 316-320 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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