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Effects of Endogenous Toxic Substance (sphingosine) on the Aging of the Nervous System

Research Project

Project/Area Number 01480241
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Neurology
Research InstitutionKyushu University

Principal Investigator

GOTO Ikuo  Kyushu University, Faculty of Medicine, Professor, 医学部, 教授 (20038631)

Co-Investigator(Kenkyū-buntansha) KOBAYASHI Takuro  Kyushu University, Faculty of Medicine, Lecturer, 医学部, 講師 (40158902)
Project Period (FY) 1989 – 1990
Project Status Completed (Fiscal Year 1990)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 1990: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1989: ¥5,800,000 (Direct Cost: ¥5,800,000)
Keywordssphingosine / galactosylsphingosien / lysosulfatide / lysoganglioside / endogenoustoxic substance / aging
Research Abstract

As to the etiology of the aging of the nervous system, we have studied on the effects of endogenous toxic substance. In this project, we looked at the lysosphingolipids, especially sphingosine, which are devoid of fatty acids in the sphingolipid molecule, abundant lipids in the nervous tissues. Lysosphingolipids are so toxic because of the absence of fatty acids and the presence of free amino base, that cells are killed by a few uM of the lipids. Recently we have developed a sensitive assay method of these lysosphingolipids including sphingosine, galactosylsphingosine and lysosulfatide, using high-performance liquid chromatography, and demonstrated the natural occurrence of these compounds in normal nervous tissues. Among them, sphingosine was the most abundant and the tissue concentration was about 100 pmol/mg protein. We investigated the detoxication mechanism of this highly toxic substance and found that sphingosine is very rapidly acylated to form ceramide which is no longer cytoto … More xic. When the sphingosine was incubated with UDP-glucose or UDP-galactose in the presence of microsomes, glucosylsphingosine and galactosylsphingosine were synthesized, respectively, which are still toxic, buy the reaction rate was very slow and the Km values were high, indicating that the main pathway of the sphingosine metabolism was acylation rather than glycosylation.
It has been known that lysoganglioside GM2 is accumulated in the brain of patients with GM2 gangliosidosis. We have developed a sensitive assay method of monosialo lysogangliosides using HPLC. This method is essentially the same as for the assay method of sphingosine. Using the method, We found the natural occurrence of lysoganglioside GM1 in human, murine and bovine brain at a concentration of 0.2-2 pmol/mg protein. In the brain from patients with GM1 and GM2 gangliosidosis, several hundred times more accumulation of lyso GM1 and GM2, respectively, were observed.
Chronological study of the concentration of the lysosphingolipids revealed that galactosylsphingosine concentration increased with age but that of sphingosine did not change with age. Less

Report

(3 results)
  • 1990 Annual Research Report   Final Research Report Summary
  • 1989 Annual Research Report
  • Research Products

    (32 results)

All Other

All Publications (32 results)

  • [Publications] Toda,K.: "Accumulation of lysosulfatide(sulfogalactosylsphingosine)in tissues of a boy with metachromatic leukodystrophy." Biochem.Biophys.Res.Commun.159. 605-611 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tanaka,K.: "The twitcher mouse: accumulation of galactosylsphingosine and pathology of the central nervous system" Brain Res.482. 347-350 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tanaka,K: "The twitcher mouse:attenuated processed of Schwann cells in unmyelinated fibers" Brain Res.503. 160-162 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Mitsuo,K.: "Biosynthesis of galactosylsphingosin(psychosine)in the twitcher mouse" Neurochem.Res.14. 1191-1194 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kobayashi,T.: "Metabolism of free sphingoid bases in murine tissues and in cultured human fibroblasts." Eur.J.Biochem. 186. 493-499 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Mitsuo,K.: "Juvenile Sandhoff disease: A Japanese patient carrying a mutation identical to that found earlier in a Canadian patient" J.Neural.Sci.98. 227-286 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yoshimura,T.: "Decreased fatty acylation of myelin proteolipid protein in the twitcher mouse." J.Neurochem. 55. 836-841 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Toda,K.: "Lysosulfatide(sulfogalactosylsphingosine)accumulation in tissues from patients with metachromatic leukodystrophy." J.Neurochem.55. 1585-1591 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yoshimura,T.: "Accumulation of galactosylsphingosine(psychosine)does not interfere with phosphorylation and methylation of myelin basic protein in the twitcher mouse" Neurochem.Res.15. 963-967 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kobayashi,T.: "A sensitive assay of lysoganglisides using highーperformance liquid chromatography" Biochim.Biophys Acta.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Toda K: "Accumulation of lysosulfatide (sulfogalactosylsphingosine) in tissues of a boy with metachromatic leukodystrophy" Biochem Biophys Res Commun. 159. 605-611 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tanaka K: "The twitcher mouse : accumulation of galactosylsphingosine and pathology of the central nervous system" Brain Res. 482. 347-350 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Tanaka K: "The twitcher mouse mouse : attenuated processed of Schwann cells in unmyenated fibers" Brain Res. 503. 160-162 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Mitsuo K: "Biosynthesis of galactosylsphingosine (psychosine) in the twitcher mouse" Neurochem Res. 14. 1191-1194 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kobayashi T: "Metabolism of free sphingoid bases in murine tissues and in cultured human fibroblasts" Eur J Biochem. 186. 493-499 (1989)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Mitsuo K: "Juvenile Sandhoff disease : A Japanese patient carrying a mutation identical to that found earlier in a Canadian patient" J Neurol Sci. 98. 277-286 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yoshimura T: "Decreased fatty acylation of myelin proteolipid protein in the twitcher mouse" J Neurochem. 52. 836-841 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Toda K: "Lysosulfatide (sulfogalactosylsphingosine) accumulation in tissues from patients with metachromatic leukodystrophy" J Neurochem. 55. 1585-1591 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Yoshimura T: "Accumulation of galactosylsphingosine (psychosine) does not interfere with phosphorylation and methylation of myelin basic protein the twitcher mouse" Neurochem Res. 15. 963-967 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Kobayashi T: "A sensitive assay of lysogangliosides using high-performance liquid chromatography" Biochim Biophys Acta.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1990 Final Research Report Summary
  • [Publications] Mitsuo,K.: "Juvenile Sandhoff disease:A Japanese patient carrying a mutation identical to that found earlier in a Canddian patient" J.Neurol.Sci.98. 277-286 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Yoshimura,T.: "Decreased fatty acylation of myelin proteolipid protein in the twitcher mouse" J.Neurochem.52. 836-841 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Toda,K.: "Lysosulfatide (sulfogalactosylsphingosine) accumulation in tissues from patients with metachromatic leukodystrophy" J.Neurochem.55. 1585-1591 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Yoshimura,T.: "Accumulation of galactosylsphingosine (psychosine) does not interfere with phosphorylation and methylation of myelin basic protein in the twitcher mouse" Neurochem.Res.15. 963-967 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Kobayashi,T.: "A sensitive assay of lysogangliosides using high performance liquied chromatography" Biochim.biophys.Acta.

    • Related Report
      1990 Annual Research Report
  • [Publications] Tanaka,K.et al.: "The twitcher mouse:accumulation of galactosylsphingosine and pathology of the central nervous system" Brain Res.482. 347-350 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Yoshimura,T.et al.: "Decreased fatty acylation of myelin proteolipid protein in the twitcher mouse" J.Neurochem. 52. 836-841 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Toda,K.et al.: "Accumulation of lysosulfatide(sulfogalactosyl sphingosine)in tissues of a boy with metachromatic leukodystrophy" Biochem.Biophys.Res.Commun.159. 605-611 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Mitsuo,K.et al.: "Biosynthesis of galactosylsphingosine(psychosine)in the twitcher mouse" Neurochem.Res.14. 899-903 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Tanaka,K.et al.: "The twitcher mouse:attenuated processes of Schwann cells in unmyelinated fibers." Brain Res.503. 160-162 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Kobayashi,T.et al.: "Metabolism of free sphingoid bases in murine tissues and in cultured human fibroblasts." Eur.J.Biochem.186. 493-499 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Kobayashi,T.et al.: "Lipid Storage Disorders" Plenum Press,N.Y., 284 (1988)

    • Related Report
      1989 Annual Research Report

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Published: 1989-04-01   Modified: 2016-04-21  

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