2000 Fiscal Year Annual Research Report

SODの細胞内局在性に基づく家族性筋萎縮性側策硬化症の発症機構の解析

Research Project

Project/Area Number	12210130
Research Institution	Osaka City University
Principal Investigator	佐藤英介大阪市立大学, 医学部, 助手 (60211942)
Keywords	家族性筋萎縮性側策硬化症 / 活性酸素 / ミトコンドリア / ペルオキシソーム / カルニチン / スーパーオキシドヂスムターゼ
Research Abstract	筋萎縮性側索硬化症(ALS)は中年期以降に発症する進行性の運動ニューロン変性疾患であり、この約5〜10%は常染色体優性遺伝による家族性筋萎縮性側索硬化症(FALS)である。FALS発症にはCu/Zn-SODの点突然変異が関与することは判明したが、その分子関連は不明である。これまで、青森県のFALS患者のSOD1遺伝子構造と赤血球内のSOD1の活性及び酵素化学的解析を行い、様々な物性変化を明らかにした。他の変異SODとの比較解析から、本病態の解明には分子物性のみならず、SOD1の細胞内超微局在性を明らかにする必要があることが判明した。ミトコンドリアやペルオキシゾームが細胞内における活性酸素産生の主な場であることに注目し、両オルガネラとSOD1の細胞内相互作用を解析して、本疾患における活性酸素代謝の場の異常が発症機構に関与する可能性を明らかにした。その結果、SOD1は細胞質に存在するだけでなく、膜画分にも存在することが判明した。さらに、FALSではミトコンドリア局所での活性酸素病態が増強し、これが本オルガネラ依存性のアポトーシスを誘起すること、およびその背景に長鎖脂肪酸の内膜毒性と膜電唖消失、これに続くチトクロムc遊離が関与すること、およびその毒性がカルニチンにより抑制できることを明らかにした。現在、SOD1変異のトランスジェニックマウスの解析からin vivoでの細胞内局在と病因との関係を明らかにしつつある。

Research Products

(11 results)

All Other

All Publications (11 results)

[Publications] Takada,Y.,Sato,E.F.,Nakajima,T.,Hoxono,M.,Tsumura,M.,Inoue,M.Yamada,R.: "Granulocyte-colony stimulating factor enhances antitumor effect of hyperthermia"J.Hyperthermia. 16・3. 275-286 (2000)
[Publications] Nakamura,A.,Park,AM.,Nagata,K.,Sato,EF.,Tamura.T.,Inoue.M.: "Oxidative cellular damage associated with transformation of Helicobacter pylori from a bacillary to a coccoid form"Free Radic.Biol.Med. 28・11. 1611-1618 (2000)
[Publications] Inoue,M.,Nishikawa,M.,Sato,E.F.,Paku A.,Kashiba.M.,Takehara,Y.,Utsumi,K.: "Cross-talk between NO and oxyradicals,a supersystem that regulates energy metabolism and survival of animals"Free Radic.Res. 33・. 757-770 (2000)
[Publications] Tsuchiya,M.,Maeda,K.,E F,Sato.,Ohnishi,Y.,Shindo,M.,Asada,A.,Inoue,M.: "Propofol versus midazolam regarding their antioxidant activities"Am.J.Res.Criti.Car.Med.. 163・. 1-6 (2001)
[Publications] Goto,T.,Kono,T.,Ishii,M.,Sato.E.F.: "Supressive effects of cyclosporin A and FK-506 on superoxide generation in human polymorphonuclear leukocytes primed by TNF-a"J.Invest.Dermatol.. (in press) (2001)
[Publications] Tomita,M.,Sato,E.F.,Nishikawa,M.,Yamano.Y..Inoue.M.: "Nitric oxide regulates mitochondrial respiration and functions of articular chondrocytes"Arthritis & Rheumatism. 44・1. 96-104 (2001)
[Publications] Kira,Y.,Sato,EF.,Inoue,M.: "Association of Cu,Zn-SOD with membrane of mitochondria amd peroxisomes"Free Radic.Biol.Med. (in press). (2001)
[Publications] Nishikawa,M.,Nishiguchi,S.,Tamori,A.,Koh,N.,Takeda,T.,Shiomi,S.,Kubo,S.,Hirohashi,K.,Kinoshita,H.,Sato.E.F.,Inoue.M.: "Somatic mutation of mitochondrial DNA in cancerous and noncancerous liver tissue in individuals with hepatocellular carcinoma"Cancer Res. (in press). (2001)
[Publications] Inoue,K.,Kira.M.,Sato.E.F.,Inoue.A.,Kurahashi,S.,Yamagami,S.,Kiriike,N.,Inoue,M.: "Properties of a mutant Cu,Zn-SOD from a Japanese patient with familiar amyotrophic lateralsclerosis"Brain Res. (in press). (2001)
[Publications] Nishikawa,M.,Nagatomi,H.,Bao-Jun Chang,Sato,E.F.,Inoue,M.: "Targeting superoxide dismutase to renal proximal tuble cells inhibits mitochondrial injury and renal dysfunction induced by cisplatin"Arch.Biochem. & Biophys.. 386・2(in press). (2001)
[Publications] Nishikimi,A.,Kira,Y.,Kasahara,E.,Sato,EF.,Kanno,T.,Utsumi,K.,Inoue,M.: "Tributyltin interacts with thiol groups in adenine nucleotide translocator therby inducing cytochrome c release"Biochem,J. (in press). (2001)

2000 Fiscal Year Annual Research Report

SODの細胞内局在性に基づく家族性筋萎縮性側策硬化症の発症機構の解析

Principal Investigator

佐藤 英介 大阪市立大学, 医学部, 助手 (60211942)

Research Products

[Publications] Takada,Y.,Sato,E.F.,Nakajima,T.,Hoxono,M.,Tsumura,M.,Inoue,M.Yamada,R.: "Granulocyte-colony stimulating factor enhances antitumor effect of hyperthermia"J.Hyperthermia. 16・3. 275-286 (2000)

[Publications] Nakamura,A.,Park,AM.,Nagata,K.,Sato,EF.,Tamura.T.,Inoue.M.: "Oxidative cellular damage associated with transformation of Helicobacter pylori from a bacillary to a coccoid form"Free Radic.Biol.Med. 28・11. 1611-1618 (2000)

[Publications] Inoue,M.,Nishikawa,M.,Sato,E.F.,Paku A.,Kashiba.M.,Takehara,Y.,Utsumi,K.: "Cross-talk between NO and oxyradicals,a supersystem that regulates energy metabolism and survival of animals"Free Radic.Res. 33・. 757-770 (2000)

[Publications] Tsuchiya,M.,Maeda,K.,E F,Sato.,Ohnishi,Y.,Shindo,M.,Asada,A.,Inoue,M.: "Propofol versus midazolam regarding their antioxidant activities"Am.J.Res.Criti.Car.Med.. 163・. 1-6 (2001)

[Publications] Goto,T.,Kono,T.,Ishii,M.,Sato.E.F.: "Supressive effects of cyclosporin A and FK-506 on superoxide generation in human polymorphonuclear leukocytes primed by TNF-a"J.Invest.Dermatol.. (in press) (2001)

[Publications] Tomita,M.,Sato,E.F.,Nishikawa,M.,Yamano.Y..Inoue.M.: "Nitric oxide regulates mitochondrial respiration and functions of articular chondrocytes"Arthritis & Rheumatism. 44・1. 96-104 (2001)

[Publications] Kira,Y.,Sato,EF.,Inoue,M.: "Association of Cu,Zn-SOD with membrane of mitochondria amd peroxisomes"Free Radic.Biol.Med. (in press). (2001)

[Publications] Nishikawa,M.,Nishiguchi,S.,Tamori,A.,Koh,N.,Takeda,T.,Shiomi,S.,Kubo,S.,Hirohashi,K.,Kinoshita,H.,Sato.E.F.,Inoue.M.: "Somatic mutation of mitochondrial DNA in cancerous and noncancerous liver tissue in individuals with hepatocellular carcinoma"Cancer Res. (in press). (2001)

[Publications] Inoue,K.,Kira.M.,Sato.E.F.,Inoue.A.,Kurahashi,S.,Yamagami,S.,Kiriike,N.,Inoue,M.: "Properties of a mutant Cu,Zn-SOD from a Japanese patient with familiar amyotrophic lateralsclerosis"Brain Res. (in press). (2001)

[Publications] Nishikawa,M.,Nagatomi,H.,Bao-Jun Chang,Sato,E.F.,Inoue,M.: "Targeting superoxide dismutase to renal proximal tuble cells inhibits mitochondrial injury and renal dysfunction induced by cisplatin"Arch.Biochem. & Biophys.. 386・2(in press). (2001)

[Publications] Nishikimi,A.,Kira,Y.,Kasahara,E.,Sato,EF.,Kanno,T.,Utsumi,K.,Inoue,M.: "Tributyltin interacts with thiol groups in adenine nucleotide translocator therby inducing cytochrome c release"Biochem,J. (in press). (2001)

佐藤英介大阪市立大学, 医学部, 助手 (60211942)