Research for requirement of down-regulation of energy metabolism for neuronal differentiation

• Project/Area Number: 17500263
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Nippon Medical School
• Principal Investigator: OHSAWA Ikuroh Nippon Medical School, Institute of Gerontology, Senior Assistant Professor (30343586)
• Co-Investigator(Kenkyū-buntansha): KAMIMURA Naomi Nippon Medical School, Assistant Professor (60283800) ; OHTA Shigeo Nippon Medical School, Graduate School of Medicine, Professor (00125832)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,670,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥270,000); Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2005: ¥1,300,000 (Direct Cost: ¥1,300,000)
• Keywords: Neuroscience / Differentiation / Mitochondria / Brain / Signal transduction

Research Abstract

Only a few human neuroblastoma cell-lines maintain the potential for neuronal differentiation. We noticed by chance that differentiable human neuroblastomas including SH-SY5Y have a specific mutation in the dihydrolipoamide-succinyltransferase (DLST) gene, whose product is a component of the α-ketoglutarate-dehydrogenase complex involved in mitochondrial energy metabolism. Here we demonstrate a requirement of energy-reduction for neuronal differentiation by restoring SH-SY5Y with the wild-type DLSTgene. Up-regulation of DLST activity increased mitochondrial membrane potential and impaired neuronal differentiation. The impairment was partially rescued by treatment with inhibitors of energy metabolism. Additionally, down-regulation of DLST expression with small interfering RNA enhanced neuronal differentiation in rat pheochromocytoma PC12 and primary cultured neocortical cells. We further found that mitochondrial membrane potential among SH-SY5Y cells was heterogeneous and lower in neuroblastic type cells. It is thus concluded that the casual mutation conferred the potential for differentiation on the neuroblastomas, suggesting that such mutants had been preferentially selected as a model cell-line for neuronal differentiation. The energy-reduction seemed to contribute to the differentiation by preventing cell-death. These results provide a new insight into neuronal differentiation.

Research Products

• [Journal Article] Combination therapy with transductive anti-death FNK protein and FK506 ameliorates brain damage with focal transient ischemia in rat (2008)
  • Author(s): KATURA KI.
  • Journal Title: J.Neuchem. (In press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Glioma patient prognosis by combined immunostaining for survivin,Ki-67 and epidermal growth factor receptor (2008)
  • Author(s): Kogiku M.
  • Journal Title: J.Clin.Neurosci. (In press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] 加齢 (2008)
  • Author(s): 大澤 郁朗
  • Journal Title: アルツハイマー病-基礎研究から予防・治療の新しいパラダイム-日本臨牀増刊 66(増刊)1 Pages: 169-174
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ミトコンドリアに局在するAβ結合アルコール脱水素酵素による酸化ストレスからの防御機構 (2008)
  • Author(s): 村上 弥生
  • Journal Title: アルツハイマー病-基礎研究から予防・治療の新しいパラダイム-日本臨牀 66(増刊)1 Pages: 113-120
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Combination therapy with transductive anti-death FNK protein and FK506 ameliorates brain damage with focal transient ischemia in rat (2008)
  • Author(s): Katsura, KI., Takahashi, K., Asoh, S., Watanabe, M., Sakurazawa, M., Ohsawa, I., Mod, T., Igarashi, H., Ohkubo, S., Katayama, Y., Ohta, S
  • Journal Title: J. Neurochem doi : 10.1111/j.0022-3042.2008.05360.x
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Combination therapy with transductive anti-death FNK protein and FK506 ameliorates brain damage with focal transient ischemia in rat. (2008)
  • Author(s): KATURA KI.
  • Journal Title: J. Neuchem. (In press)
  • Peer Reviewed
• [Journal Article] Glioma patient prognosis by combined immunostaining for survivin, Ki-67 and epidermal growth factor receptor (2008)
  • Author(s): Kogiku M.
  • Journal Title: J. Clin. Neurosci. (In press)
  • Peer Reviewed
• [Journal Article] 加齢 (2008)
  • Author(s): 大澤郁朗
  • Journal Title: アルツハイマー病-基礎研究から予防・治療の新しいパラダイム- 日本臨牀 増刊 66増刊1(In press)
• [Journal Article] ミトコンドリアに局在するAβ結合アルコール脱水素酵素による酸化ストレスからの防御機構 (2008)
  • Author(s): 村上弥生
  • Journal Title: アルツハイマー病-基礎研究から予防・治療の新しいパラダイム- 日本臨牀 66増刊1(In press)
• [Journal Article] Cytoprotective role of mitochondrial amyloid beta peptide-binding alcohol dehydrogenase against a cytotoxic aldehyde (2007)
  • Author(s): Murakami Y.
  • Journal Title: Neurobiol.Aging (In press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress (2007)
  • Author(s): Fukuda K.
  • Journal Title: Biochem.Biophys.Res.Commun. 361 Pages: 670-674
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Hydrogen acts as a therapeutic antioxidant by the selective reduction of cytotoxic oxygen radicals (2007)
  • Author(s): Ohsawa I.
  • Journal Title: Nat.Med. 13 Pages: 688-694
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Glioma patient prognosis by combined immunostaining for survivin, Ki-67 and epidermal growth factor receptor (2007)
  • Author(s): Kogiku, M., Ohsawa, I., Matsumoto, K., Sugisaki, Y., Takahashi, H., Teramoto, A., Ohta, S
  • Journal Title: J. Clin. Neurosci. doi : 10.1016/j.jocn.2007.11.012
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cytoprotective role of mitochondrial amyloid beta peptide-binding alcohol dehydrogenase against a cytotoxic aldehyde (2007)
  • Author(s): Murakami, Y., Ohsawa, I., Kasahara,T., Ohta,S
  • Journal Title: Neurobiol Aging. doi : 10.1016/j.neurobiolaging. 2007.07.002
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. (2007)
  • Author(s): Fukuda, K., Asoh, S., Ishikawa, M., Yamamoto.Y., Ohsawa. I., Ohta.S
  • Journal Title: Biochem Biophys Res Commun 361 Pages: 670-674
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. (2007)
  • Author(s): Ohsawa, I., Ishikawa, M., Takahashi, K., Watanabe, M., Nishimaki, K., Yamagata, K., Katsura, Katayama, Y., Asoh, S., Ohta, S
  • Journal Title: Nat. Med 13 Pages: 688-694
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cytoprotective role of mitochondrial amyloid beta peptide-binding alcohol dehydrogenase against a cytotoxic aldehyde. (2007)
  • Author(s): Murakami Y.
  • Journal Title: Neurobiol. Aging (In press)
  • Peer Reviewed
• [Journal Article] Inhalation of hydrogen gas suppresses hepatic injury caused by ischemia/reperfusion through reducing oxidative stress. (2007)
  • Author(s): Fukuda K.
  • Journal Title: Biochem. Biophys. Res. Commun. 361 Pages: 670-674
  • Peer Reviewed
• [Journal Article] Hydrogen acts as a therapeutic antioxidant by the selective reduction of cytotoxic oxygen radicals. (2007)
  • Author(s): Ohsawa I.
  • Journal Title: Nat. Med. 13 Pages: 688-694
  • Peer Reviewed
• [Journal Article] Hydrogen acts as a therapeutic antioxidant by the selective reduction of cytotoxic oxygen radicals. (2007)
  • Author(s): Ohsawa, I.
  • Journal Title: Nat. Med. 13・5(In press)
• [Journal Article] アルツハイマー病の危険因子である酵素活性欠損型アルデヒド脱水素酵素2遺伝子-その分子メカニズムとモデル動物の開発- (2006)
  • Author(s): 大澤 郁朗
  • Journal Title: 日本認知症学会誌 19 Pages: 284-295
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Dysfunction of mitochondria and oxidative stress in the pathogenesis of Alzheimer's disease:On defects in the cytochrome c oxidase complex and aldehyde detoxification (2006)
  • Author(s): Ohta S.
  • Journal Title: J.Alzheimer's Dis. 9 Pages: 155-166
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Association of alcohol dehydrogenase 2^*1 allele with liver damage and insulin concentration in the Japanese (2006)
  • Author(s): Suzuki Y.
  • Journal Title: J.Hum.Genet. 51 Pages: 31-37
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Dysfunction of mitochondria and oxidative stress in the pathogenesis of Alzheimer's disease : On defects in the cytochrome c oxidase complex and aldehyde detoxification. (2006)
  • Author(s): Ohta, S., Ohsawa, I
  • Journal Title: J. Alzheimers Dis 9 Pages: 155-166
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of alcohol dehydrogenase 2*1 allele with liver damage and insulin concentration in the Japanese. (2006)
  • Author(s): Suzuki, Y., Ando, F., Ohsawa, I., Shimokata, H., Ohta, S
  • Journal Title: J. Hum. Genet 51 Pages: 31-37
  • NAID: 10020558185
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Dysfunction of mitochondria and oxidative stress in the pathogenesis of Alzheimer's disease : On defects in the cytochrome c oxidase complex and aldehyde detoxification. (2006)
  • Author(s): Ohta, S.
  • Journal Title: J. Alzheimer's Dis. 9・2 Pages: 155-166
• [Journal Article] association of alcohol dehydrogenase 2*1 allele with liver damage and insulin concentration in the Japanese. (2006)
  • Author(s): Suzuki, Y.
  • Journal Title: J. Hum. Genet. 51・1 Pages: 31-37
• [Journal Article] Association of alcohol dhydrogenase 2*1 allele with liver damage and insulin concentration in the Japanese. (2006)
  • Author(s): Suzuki, Y.
  • Journal Title: J. Hum. Genet. 51・1 Pages: 31-37
• [Journal Article] Prognostic significance of the immunohistochemical index of survivin in glioma:a comparative study with the MIB-1 index (2005)
  • Author(s): Uematsu M.
  • Journal Title: J.Neurooncol. 72 Pages: 231-238
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] The anti-cell death FNK protein protects cells from death induced by freezing and thawing (2005)
  • Author(s): Sudo K.
  • Journal Title: Biochem.Biophys.Res.Commun. 330 Pages: 850-856
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Various morphologies of mitochondria (2005)
  • Author(s): Ohsawa I.
  • Journal Title: J.Nippon Med.Sch. 72 Pages: 136-136
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Aggregation of mitochondria (2005)
  • Author(s): Aokage T.
  • Journal Title: J.Neurooncol. 72 Pages: 72-73
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] ミトコンドリアの老化への関与とその機能異常 (2005)
  • Author(s): 大澤 郁朗
  • Journal Title: Molecular Medicine 39 Pages: 520-526
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Prognostic significance of the immunohistchemical index of surviving in glioma : A comparative study with the MIB-1 index. (2005)
  • Author(s): Uematsu, M., Ohsawa, I., Aokage, T., Nishimaki, K., Matsumoto, K., Takahashi H., Asoh, S., Teramoto A, Ohta S
  • Journal Title: J. Neuro-Oncology 72 Pages: 231-238
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The anti-cell death FNK protein protects cells from death induced by freezing and thawing. (2005)
  • Author(s): Sudo, K., Asoh, S., Ohsawa, I., Ozaki, D., Yamagata, K., Ito, H., Ohta, S
  • Journal Title: Biochem. Biophys. Res. Commun 330 Pages: 850-856
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Various morphologies of mitochondria (2005)
  • Author(s): Ohsawa, I., Aokage, T., Ohta, S
  • Journal Title: J Nippon Med Sch 72 Pages: 136-136
  • NAID: 130004057279
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Aggregation of mitochondria (2005)
  • Author(s): Aokage, T, Ohsawa, I., Ohta, S
  • Journal Title: J Nippon Med Sch 72 Pages: 72-73
  • NAID: 130004146787
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] アルツハイマー病の危険因子である酵素活性欠損型アルデヒド脱水素酵素2遺伝子 (2005)
  • Author(s): 大澤郁朗
  • Journal Title: 日本認知症学会誌 19・3 Pages: 284-296
• [Journal Article] Various morphologies of mitochondria (2005)
  • Author(s): Ohsawa, I.
  • Journal Title: J. Nippon Med. Sch. 72・3 Pages: 136-136
• [Journal Article] Aggregation of Mitochondria (2005)
  • Author(s): Aokage, T.
  • Journal Title: J. Nippon Med. Sch. 72・2 Pages: 72-73
• [Journal Article] Prognostic significance of the immunohistochemical index of survivin in glioma : a comparative study with the MIB-1 index (2005)
  • Author(s): Uematsu, M.
  • Journal Title: J. Neurooncol. 72・3 Pages: 231-238
• [Journal Article] The anti-cell death FNK protein protects cells from death indeuced by freezing and thawing (2005)
  • Author(s): Sudo, K.
  • Journal Title: Biochem. Biophys. Res. Commun. 330・3 Pages: 850-856
• [Presentation] 新しい抗酸化治療法:細胞傷害性酸素ラジカルの水素による選択的還元 (2007)
  • Author(s): 大澤 郁朗
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 新しい抗酸化治療法:細胞障害性酸素ラジカルの水素による選択的還元 (2007)
  • Author(s): 大澤郁朗
  • Organizer: BMB2007
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-11
• [Presentation] The role of mitochondrial amyloid beta peptide-binding alcohol dehydrogenease(ABAD)in detoxification of toxic aldehydes in Alzheimer's disease (2007)
  • Author(s): 大澤 郁朗
  • Organizer: The 8th Asia/Oceania Regional Congress of Gerontology and Geriatrics
  • Place of Presentation: Beijing,China
  • Year and Date: 2007-10-23
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The role of mitochondrial amyloid beta peptide-binding alcohol dehydrogenease(ABAD)in detoxification of toxic aldehydes in Alzheimer's disease. (2007)
  • Author(s): 大澤郁朗
  • Organizer: The 8th Asia/Oceania Regional Congress of Gerontology and Geriatrics
  • Place of Presentation: 北京
  • Year and Date: 2007-10-23
• [Presentation] Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals in the nervous system (2007)
  • Author(s): 大澤 郁朗
  • Organizer: IPA 2007 Osaka Silver Congress
  • Place of Presentation: 大阪
  • Year and Date: 2007-10-17
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals in the nervous system. (2007)
  • Author(s): 大澤郁朗
  • Organizer: IPA 2007 Osaka Silver Congress
  • Place of Presentation: 大阪
  • Year and Date: 2007-10-17
• [Presentation] The role of mitochondrial amyloid beta peptide-binding alcohol dehydrogenease (ABAD) in detoxification of toxic aldehydes in Alzheimer's disease. (2007)
  • Author(s): Ohsawa, I
  • Organizer: The 8th Asia/Oceania Regional Congress of Gerontology and Geriatrics
  • Place of Presentation: Beijing China
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals in the nervous system. (2007)
  • Author(s): Ohsawa, I., Ishikawa, M., Takahashi, K., Watanabe, M., Nishimaki, K., Yamagata, K., Katsura,K.-I., Asoh, S., Ohta, S
  • Organizer: IPA 2007 Osaka Silver Congress
  • Place of Presentation: Osaka Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Role of Mitochondrial aldehyde dehydrogenase in the onset of Alzheimer's Disease (2006)
  • Author(s): 大澤 郁朗
  • Organizer: The 10th Intemational Conference on Alzheimer's Disease and Related Disorders
  • Place of Presentation: Madrid,Spain
  • Year and Date: 2006-07-19
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Neurodegeneration in mice expressing a dominant negative form of mitochondrial aldehyde dehydrogenase (2006)
  • Author(s): 大澤 郁朗
  • Organizer: 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress
  • Place of Presentation: 京都
  • Year and Date: 2006-06-20
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Role of Mitochondrial aldehyde dehydrogenase in the onset of Alzheimer's Disease (2006)
  • Author(s): Ohsawa, I., Nishimaki, K., Murakami, Y., Suzuki, Y., Ishikawa, M., Ohta, S
  • Organizer: The 10th International Conference on Alzheimer's Disease and Related Disorders
  • Place of Presentation: Madrid Spain
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Neurodegeneration in mice expressing a dominant negative form of mitochondrial aldehyde dehydrogenase. (2006)
  • Author(s): Ohsawa, I., Nishimaki, K., Murakami, Y., Suzuki, Y., Ishikawa, M., Ohta, S
  • Organizer: 20th IUBMB International Congress of Biochemistry and Molecular Biology and 11th FAOBMB Congress
  • Place of Presentation: Kyoto Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Deficiency in a mitochondrial aldehyde dehydrogenase promotes oxidative stress and the onset of Alzheimer's disease:Its molecular mechanisms and animal models (2005)
  • Author(s): 大澤 郁朗
  • Organizer: International Conference on Mitochondria and Life 2005
  • Place of Presentation: 東京
  • Year and Date: 2005-12-17
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 水素分子(H_2)による酸化ストレス細胞死の抑制 (2005)
  • Author(s): 大澤 郁朗
  • Organizer: 第78回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2005-10-21
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Deficiency in a mitochondrial aldehyde dehydrogenase promotes oxidative stress and the onset of Alzheimer's disease : Its molecular mechanisms and animal models (2005)
  • Author(s): Ohsawa, I., Nishimaki, K., Murakami, Y., Suzuki, Y., Ishikawa, M., Ohta, S
  • Organizer: International Conference on Mitochondria and Life 2005
  • Place of Presentation: Tokyo Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 酸化ストレスナビゲーター(監修倉林正彦) (2005)
  • Author(s): 大澤 郁朗(分担)
  • Total Pages: 331
  • Publisher: メディカルビュー社
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 酸化ストレスナビゲーター (2005)
  • Author(s): 倉林正彦
  • Total Pages: 331
  • Publisher: メディカルビュー社
• [Remarks] 「研究成果報告書概要(和文)」より
  • URL: http://www.nms.ac.jp/ig/biocell/
• [Remarks]
  • URL: http://www.nms.ac.jp/ig/biocell/
• [Patent(Industrial Property Rights)] 生体内の有害なフリーラジカル除去剤 (2005)
  • Inventor(s): 太田 成男・大澤 郁朗・室田 渉
  • Industrial Property Rights Holder: 太田 成男・大澤 郁朗・室田 渉
  • Industrial Property Number: 2005-238572
  • Filing Date: 2005-08-19
  • Description: 「研究成果報告書概要(和文)」より
• [Patent(Industrial Property Rights)] 酸化ストレスに伴う老化関連疾患を示すトランスジェニック動物 (2005)
  • Inventor(s): 太田 成男・大澤 郁朗・西槙 貴代美
  • Industrial Property Rights Holder: 日本医科大学
  • Filing Date: 2005-03-10
  • Description: 「研究成果報告書概要(和文)」より
  • Overseas
• [Patent(Industrial Property Rights)] 生体内の有害なフリーラジカル除去剤 (2005)
  • Inventor(s): 太田成男, 大澤郁朗, 室田 渉
  • Industrial Property Rights Holder: 太田成男, 大澤郁朗, 室田 渉
  • Industrial Property Number: 2005-238572
  • Filing Date: 2005