1996 年度実績報告書

運動ニューロン疾患発症機序の分子生物学的研究

研究課題

研究課題/領域番号	07044232
研究機関	東京医科歯科大学
研究代表者	飯田静夫東京医科歯科大学, 医学部, 教授 (00009987)
研究分担者	ROBERT K.Yu Dept. of Biochemistry and Molecular Bioph, 教授瀧孝雄東京医科歯科大学, 医学部, 助教授 (10046295)
キーワード	運動ニューロン / 免疫精神経疾患 / 抗糖脂質抗体 / 糖脂質 / 自己抗体 / 神経系
研究概要	運動ニューロン疾患は運動ニューロンが変性、脱落し進行性の四肢麻痺を来し死に至る難病である。病院として免疫学的異常が示唆されているがその本態は不明である。一方,神経組織にある糖脂質は神経の分化、機能維持に重要な役割を果たしていることが明らかにされ来た。我々は,多くの免疫性神経疾患に抗糖脂質抗体が出現することを見い出し,この抗体が神経組織に作用して疾患を惹き起こすことを提唱した。本研究では(1)発症機構を分子レベルで解明するため,運動ニューロンに特異的な糖脂質の発現と構造及び機能(2)発症に関連する抗糖脂質抗体産生の機序(3)抗糖脂質抗体の神経系に対する作用、を中心に研究を進めた。その結果、運動ニューロン疾患の発症機序を分子レベルで解明すると云う目的に対して、多くの免疫性神経疾患で抗糖脂質抗体が出現し、この抗体が神経組織に作用して疾患を惹き起こすことをある程度実証することが出来た。ギランバレー症候群やフィッシャー症候群のかなりな数の患者では先行感染した菌の菌体成分のLPSが末梢神経の構成成分である糖脂質のガングリオシドと分子相同性を持ち、このため感染菌に対して産生された抗体が自己抗体として神経を傷害することが明らかにされた。また末梢神経系に特異的に分布するグルクロン酸を含む硫酸化糖脂質に対する抗体が産生され、同様に神経系に対する自己抗体として作用し、発症するいくつかの疾患が明らかにされた。こうした抗体を作用させると神経系の機批害を起こすことも実証された。これらの成果を挙げるためにごく微量の糖脂質を免疫化学的、構造化学的に分析、解析する新しい方法が開発され、神経系における糖脂質の構造、分布を明らかにした。また培養系で血液-脳・末梢神経関門モデルを作製することに成功し、この系を用いて自己抗体による神経障害の起こる機序を解明出来るようになった。

研究成果

(29件)

すべてその他

すべて文献書誌 (29件)

[文献書誌] Ariga T.et al: "Expression and localization of Lewis(x) glycolipids and GD-la ganglioside in human glioma cells." Glycoconjugate J.13(2). 135-45 (1996)
[文献書誌] Isobe T.et al: "A simple assay method for bacterial binding to glycosphingolipids on a polyvinylidene difluoride membrane after thin-layer chromatography blotting and in situ mass spectrometric analysis of the ligands." Anal.Biochem.236. 35-40 (1996)
[文献書誌] Kasama T. et al: "Microscale analysis of glycosphingolipids by TLC blotting/secondary ion mass spectrometry : a novel blood group A-activeglycosphigolipid and change in glycosphingolipid expression in rat mammary tumor cells with different metastatic potential." Glycoconjugate J.13. 461-69 (1996)
[文献書誌] Mizushima N et al: "Ceramide induces apoptosis via CPP32 activation." FEBS lett. 395. 267-71 (1996)
[文献書誌] Tadano AK et al: "Structural characterization of a novel mono-sulfated gangliotrinosylceramide containing a 3-O-sulfated N-acetylgalactosamine from rat kidney." Glycoconjugate J.13. 285-93 (1996)
[文献書誌] Taki T et al: "[Cancer-associated alterations of glycoconjugates・・special reference to glycosphingolipids].[Review]" Nippon Geka Gakkai Zasshi.97. 123-30 (1996)
[文献書誌] Yoshida S.et al: "Lysophosphatidic acid and bFGF control different modes in proliferating myoblasts." J.Cell Biol.132. 181-93 (1996)
[文献書誌] Yuki N.et al: "Autoantibodies to peripheral nerve glycosphingolip ids SPG,SLPG,and SGPG in Guillian-Barre syndrome and chronic inflamatory demyelinating polyneurophathy." J.Neuroimm.70. 1-6 (1996)
[文献書誌] Yuki N.et al: "Antibody to GalNAc-GD1a and GalNAc-GM1b in Guillian-Barre syndrome subsequent to Campylobacter jejuni enteritis." J.Neuroimm.71. 155-61 (1996)
[文献書誌] Watarai S.et al: "Isolation and characterization of gangliosides from Theileria sergenti." J.Vet.Med.Sci.58(11). 1099-105 (1996)
[文献書誌] Ariga T.et al: "Glycosphingolipid composition of murine neuroblastoma cells : O-acetylesterase gene downregulates the expression of O-acetylated GD3." Biochemistry. 34. 11500-7 (1995)
[文献書誌] Ariga T.et al: "Accumulation of isoglobosode and ganglio-N-tetraosyl ceramide having blood group B determinant in the hepatomas of female LEC rats." Biochim. Biophys. Acta. 1254. 257-66 (1995)
[文献書誌] Ariga T.et al: "Expression and localization of Lewis(x) glycolipids and GD1a ganglioside in human glioma cells." Glycoconjugate J.13. 133-45 (1996)
[文献書誌] Ben Y.et al: "Anti-sulfoglucuronyl paragloboside IgM antibodies in amyotrophic lateral sclerosis." J.Neuroimmunol.57. 111-5 (1995)
[文献書誌] Freischutz B.: "Characterization of sialyltransfrerase-IV activity and its involvement in the c-pathway of brain ganglioside metabolism." J.Neurochem.64. 385-93 (1995)
[文献書誌] Gao L.et al: "Association of a 14-3-3 protein with CMP-NeuAc : GM1 alpha 2,3-sialyltransferase." Biochem.Biophysi Res.Commu.224. 103-7 (1996)
[文献書誌] Gu X.et al: "Regulation of sialyltransferase activities by phosphorylation and dephosphorylation." J.Neurochem.64. 2295-302 (1995)
[文献書誌] Kanda T.et al: "Interleukin 1 beta up-regulates the expression of sulfoglucuronosyl paragloboside,a ligand for L-selectin,in brain microvascular endothelial cells." Proc.Natl.Acad.Sci.U.S.A.92. 7897-901 (1995)
[文献書誌] Kanda T.et al: "Effect of nerve growth factor and forskolin on glycosyltransferase activities and expression of a globo-series glycosphingolipid in PC12D pheochromocytoma cells." J.Neurochem.64. 810-7 (1995)
[文献書誌] Pal S.et al: "Expression of a unique globo-series glycolipid in cultured rat dorsal root ganglion neurons : relationship with neuronal development." Neurochem.Res.21. 403-9 (1996)
[文献書誌] Ritter G.et al: "Analysis of the antibody response to immunization with purified O-acetyl GD3 gangliosides in patients with malignant melanoma." Intl.J.Cancer. 62. 668-72 (1995)
[文献書誌] Saito M.et al: "Characterization of sialidase activity in mouse synaptic plasma membranes and its age-related changes." J.Neurosci.40. 401-6 (1995)
[文献書誌] Yamawaki M.et al: "Generation and characterization of antisulfoglucuronosyl paragloboside monoclonal antibody NGR50 and its immunoreactivity with peripheral nerve." J.Neurosci.Res.44. 586-93 (1996)
[文献書誌] Yamawaki M.et al: "Sensitization of Lewis rats with sulfoglucuronosyl paragloboside : electrophysiological and immunological studies of an animal model of peripheral neuropathy." J.Neurosci.Res.44. 58-65 (1996)
[文献書誌] Zeng G.et al: "Regulation of glycolipid synthesis in HL-60 cells by antisense oligodeoxynucleotides to glycosyltransferase sequences : effect on cellular differentiation." Proc.Natl.Acad.Sci.U.S.A.92. 8670-4 (1995)
[文献書誌] Zeng G.et al: "Molecular cloning of cDNA for rat brain GD3-synthase." Biochem.Biophys.Res.Commu.226. 319-23 (1996)
[文献書誌] Newman,S.et al: "Biochemistry of myelin proteins and enzymes." In Neuroglial cells.535-54 (1995)
[文献書誌] Saito,M.et al: "Biochemistry and function of sialidases." In Biology od sialic acids.261-313 (1995)
[文献書誌] Saito,M.et al: "Glycolipids of the CNS" In Molecilar biology og multiple sclerosis.219-29 (1997)

1996 年度 実績報告書

運動ニューロン疾患発症機序の分子生物学的研究

研究代表者

飯田 静夫 東京医科歯科大学, 医学部, 教授 (00009987)

研究成果

[文献書誌] Ariga T.et al: "Expression and localization of Lewis(x) glycolipids and GD-la ganglioside in human glioma cells." Glycoconjugate J.13(2). 135-45 (1996)

[文献書誌] Isobe T.et al: "A simple assay method for bacterial binding to glycosphingolipids on a polyvinylidene difluoride membrane after thin-layer chromatography blotting and in situ mass spectrometric analysis of the ligands." Anal.Biochem.236. 35-40 (1996)

[文献書誌] Mizushima N et al: "Ceramide induces apoptosis via CPP32 activation." FEBS lett. 395. 267-71 (1996)

[文献書誌] Tadano AK et al: "Structural characterization of a novel mono-sulfated gangliotrinosylceramide containing a 3-O-sulfated N-acetylgalactosamine from rat kidney." Glycoconjugate J.13. 285-93 (1996)

[文献書誌] Taki T et al: "[Cancer-associated alterations of glycoconjugates・・special reference to glycosphingolipids].[Review]" Nippon Geka Gakkai Zasshi.97. 123-30 (1996)

[文献書誌] Yoshida S.et al: "Lysophosphatidic acid and bFGF control different modes in proliferating myoblasts." J.Cell Biol.132. 181-93 (1996)

[文献書誌] Yuki N.et al: "Autoantibodies to peripheral nerve glycosphingolip ids SPG,SLPG,and SGPG in Guillian-Barre syndrome and chronic inflamatory demyelinating polyneurophathy." J.Neuroimm.70. 1-6 (1996)

[文献書誌] Yuki N.et al: "Antibody to GalNAc-GD1a and GalNAc-GM1b in Guillian-Barre syndrome subsequent to Campylobacter jejuni enteritis." J.Neuroimm.71. 155-61 (1996)

[文献書誌] Watarai S.et al: "Isolation and characterization of gangliosides from Theileria sergenti." J.Vet.Med.Sci.58(11). 1099-105 (1996)

[文献書誌] Ariga T.et al: "Glycosphingolipid composition of murine neuroblastoma cells : O-acetylesterase gene downregulates the expression of O-acetylated GD3." Biochemistry. 34. 11500-7 (1995)

[文献書誌] Ariga T.et al: "Accumulation of isoglobosode and ganglio-N-tetraosyl ceramide having blood group B determinant in the hepatomas of female LEC rats." Biochim. Biophys. Acta. 1254. 257-66 (1995)

[文献書誌] Ariga T.et al: "Expression and localization of Lewis(x) glycolipids and GD1a ganglioside in human glioma cells." Glycoconjugate J.13. 133-45 (1996)

[文献書誌] Ben Y.et al: "Anti-sulfoglucuronyl paragloboside IgM antibodies in amyotrophic lateral sclerosis." J.Neuroimmunol.57. 111-5 (1995)

[文献書誌] Freischutz B.: "Characterization of sialyltransfrerase-IV activity and its involvement in the c-pathway of brain ganglioside metabolism." J.Neurochem.64. 385-93 (1995)

[文献書誌] Gao L.et al: "Association of a 14-3-3 protein with CMP-NeuAc : GM1 alpha 2,3-sialyltransferase." Biochem.Biophysi Res.Commu.224. 103-7 (1996)

[文献書誌] Gu X.et al: "Regulation of sialyltransferase activities by phosphorylation and dephosphorylation." J.Neurochem.64. 2295-302 (1995)

[文献書誌] Kanda T.et al: "Interleukin 1 beta up-regulates the expression of sulfoglucuronosyl paragloboside,a ligand for L-selectin,in brain microvascular endothelial cells." Proc.Natl.Acad.Sci.U.S.A.92. 7897-901 (1995)

[文献書誌] Kanda T.et al: "Effect of nerve growth factor and forskolin on glycosyltransferase activities and expression of a globo-series glycosphingolipid in PC12D pheochromocytoma cells." J.Neurochem.64. 810-7 (1995)

[文献書誌] Pal S.et al: "Expression of a unique globo-series glycolipid in cultured rat dorsal root ganglion neurons : relationship with neuronal development." Neurochem.Res.21. 403-9 (1996)

[文献書誌] Ritter G.et al: "Analysis of the antibody response to immunization with purified O-acetyl GD3 gangliosides in patients with malignant melanoma." Intl.J.Cancer. 62. 668-72 (1995)

[文献書誌] Saito M.et al: "Characterization of sialidase activity in mouse synaptic plasma membranes and its age-related changes." J.Neurosci.40. 401-6 (1995)

[文献書誌] Yamawaki M.et al: "Generation and characterization of antisulfoglucuronosyl paragloboside monoclonal antibody NGR50 and its immunoreactivity with peripheral nerve." J.Neurosci.Res.44. 586-93 (1996)

[文献書誌] Yamawaki M.et al: "Sensitization of Lewis rats with sulfoglucuronosyl paragloboside : electrophysiological and immunological studies of an animal model of peripheral neuropathy." J.Neurosci.Res.44. 58-65 (1996)

[文献書誌] Zeng G.et al: "Regulation of glycolipid synthesis in HL-60 cells by antisense oligodeoxynucleotides to glycosyltransferase sequences : effect on cellular differentiation." Proc.Natl.Acad.Sci.U.S.A.92. 8670-4 (1995)

[文献書誌] Zeng G.et al: "Molecular cloning of cDNA for rat brain GD3-synthase." Biochem.Biophys.Res.Commu.226. 319-23 (1996)

[文献書誌] Newman,S.et al: "Biochemistry of myelin proteins and enzymes." In Neuroglial cells.535-54 (1995)

[文献書誌] Saito,M.et al: "Biochemistry and function of sialidases." In Biology od sialic acids.261-313 (1995)

[文献書誌] Saito,M.et al: "Glycolipids of the CNS" In Molecilar biology og multiple sclerosis.219-29 (1997)

1996 年度実績報告書

飯田静夫東京医科歯科大学, 医学部, 教授 (00009987)