Molecular mechanisms of neuronal death induced by endoplasmic reticulum stress.

• Project/Area Number: 14208093
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: University of Miyazaki (2004); Nara Institute of Science and Technology (2002-2003)
• Principal Investigator: IMAIZUMI Kazunori University of Miyazaki, Faculty of Medicine, Professor, 医学部, 教授 (90332767)
• Project Period (FY): 2002 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥43,810,000 (Direct Cost: ¥33,700,000、Indirect Cost: ¥10,110,000); Fiscal Year 2004: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000); Fiscal Year 2003: ¥15,210,000 (Direct Cost: ¥11,700,000、Indirect Cost: ¥3,510,000); Fiscal Year 2002: ¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000)
• Keywords: Endoplasmic reticulum stress / Neuronal death / OASIS / Neurodegenerative disorder / Transcription factor / Autophagy / オートファジー / 神経細胞死 / カスペース

Research Abstract

To study the molecular mechanisms underlying the endoplasmic reticulum(ER) stress response, we screened genes whose expression was induced during ER stress. We identified MDG1/ERdj4, a member of the DnaJ protein family, and OASIS, a member of CREB/ATF family. From the biological analyses, we demonstrated that MDG1/ERdj4 plays roles in stabilizing GRP78/BiP binding to unfolded substrate proteins in a J domain-dependent manner and preventing the accumulation of unfolded proteins in the ER. OASIS is cleaved at the membrane in response to ER stress and its cleaved N-terminal cytoplasmic domain, which contains the bZIP domain, translocates into the nucleus, and then activates transcription of target genes via direct binding to the ER stress responsive element 3, the ATF6 site and the cyclic AMP responsive element(CRE). Intriguingly, OASIS is induced at the transcriptional level during ER stress specifically in astrocytes of the central nervous system. These results reveal pivotal roles for OASIS in modulation of the astrocyte-specific unfolded protein response ; with possibilities that cell type-specific UPR signaling also exists in other cells.

Research Products

• [Journal Article] OASIS, a CREB/ATF family member, modulates the UPR signaling in astrocytes. (2005)
  • Author(s): Kondo, S., Murakami, T., Ogata, M., Kanemoto, S., Otori, K., Iseki, K., Tatsumi, K., Wanaka, A., Imaizumi, K.
  • Journal Title: Nature Cell Biology 7 Pages: 186-194
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Critical role for DP5/Harakiri, a Bcl-2 homology domain 3-only Bcl-2 family member, in axotomy-induced neuronal cell death. (2004)
  • Author(s): Imaizumi, K., Benito, A., Kiryu-Seo, S., Gonzalez, V., Inohara, N., Leiberman, A., P., Kiyama, H., Nunez, G.
  • Journal Title: Journal of Neuroscience 24 Pages: 3721-3725
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of regulatory cis-acting elements for alternative splicing of presenilin-2 exon 5 under hypoxic stress conditions. (2004)
  • Author(s): Higashide, S., Morikawa, K., Okumura, M., Kondo, S., Ogata, M., Murakami, T., Yamashita, A., Kanemoto, S., Manabe, T., Imaizumi, K.
  • Journal Title: Journal of Neurochemistry 91 Pages: 1191-1198
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Ab-induced cell death. (2004)
  • Author(s): Hitomi, J., Katayama, T., Eguchi, Y., Kudo, T., Taniguchi, M., Koyama, Y., Manabe, T., Yamagishi, S., Bando, Y., Imaizumi, K., Tsujimoto, Y., Tohyama, M.
  • Journal Title: Journal of Cell Biology 165 Pages: 347-356
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Tra2b, SF2/ASF, and SRp30c modulate the function of an exonic splicing enhancer in exon 10 of tau pre-mRNA. (2004)
  • Author(s): Kondo, S., Yamamoto, N., Murakami, T., Okumura, M., Mayeda, A., Imaizumi, K.
  • Journal Title: Genes to Cells 9 Pages: 121-130
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Endoplasmic reticulum stress and neuronal death. (2004)
  • Author(s): Imaizumi, K., Tohyama, M.
  • Journal Title: Journal of Chemical Neuroanatomy 28 Pages: 49-50
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Induction of neuronal death by ER stress in Alzheimer's disease. (2004)
  • Author(s): Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T, Tohyama M.
  • Journal Title: Journal of Chemical Neuroanatomy 28 Pages: 67-78
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Expression of truncated presenilin 2 splice variant in Alzheimer's disease, bipolar disorder, and schizophrenia brain cortex. (2004)
  • Author(s): Smith, M.J., Sharples, R.A., Evin, G., McLean, C.A., Dean, B., Pavey, G., Fantino, E., Cotton, R.G., Imaizumi, K., Masters, C.L., Cappai, R., Culvenor, J.G.
  • Journal Title: Brain Research Molecular Brain Research 127 Pages: 128-135
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12. (2004)
  • Author(s): Hitomi J, Katayama T, Taniguchi M, Honda A, Imaizumi K, Tohyama M.
  • Journal Title: Neuroscience Letters 357 Pages: 127-130
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Role of ARF4L in recycling between endosomes and the plasma membrane. (2004)
  • Author(s): Katayama T, Imaizumi K, Yoneda T, Taniguchi M, Honda A, Manabe T, Hitomi J, Oono K, Baba K, Miyata S, Matsuzaki S, Takatsuji K, Tohyama M.
  • Journal Title: Cell.Mol.Neurobiol. 24 Pages: 137-147
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] JAB1 participates in unfolded protein responses by association and dissociation with IRE1. (2004)
  • Author(s): Oono K, Yoneda T, Manabe T, Yamagishi S, Matsuda S, Hitomi J, Miyata S, Mizuno T, Imaizumi K, Katayama T, Tohyama M.
  • Journal Title: Neurochem Int. 45 Pages: 765-772
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of Regulatory cis-acting elements for alternative splicing of presenilin-2 exon 5 under hypoxic stress conditions. (2004)
  • Author(s): Higashide, S., Morikawa, K., Okumura, M., Kondo, S., Ogata, M., Murakami, T., Yamashita, A., Kanemoto, S., Manabe, T., Imaizumi, K.
  • Journal Title: Journal of Neurochemistry 91 Pages: 1191-1198
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Ab-induced cell death. (2004)
  • Author(s): Hitomi, J., Katayama, T., Eguchi, Y., Kudo, T, Taniguchi, M., Koyama, Y., Manabe, T., Yamagishi, S., Bando, Y., Imaizumi, K., Tsujimoto, Y, Tohyama, M.
  • Journal Title: Journal of Cell Biology 165 Pages: 347-356
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Expression of truncated presenilin 2 splice variant in Alzheimer's disease, bipolar disorder, and schizophrenia brain cortex. (2004)
  • Author(s): Smith, M.J., Sharpies, R.A., Evin, G., McLean, C.A., Dean, B., Pavey, G., Fantino, E., Cotton, R.G., Imaizumi, K., Masters, C.L., Cappai, R., Culvenor, J.G.
  • Journal Title: Brain Res Mol Brain Res. 127 Pages: 128-135
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Ab-induced cell death. (2004)
  • Author(s): Hitomi, J., Katayama, T., Eguchi, Y., Kudo, T, Taniguchi, M., Koyama, Y., Manabe, T., Yamagishi, S., Bando, Y., Imaizumi, K., Tsujimoto, Y, Tohyama M.
  • Journal Title: Journal of Cell Biology 165 Pages: 347-356
• [Journal Article] An intronic splicing enhancer element in SMN pre-mRNA. (2003)
  • Author(s): Miyaso, H., Okumura, M., Kondo, S., Higashide, S., Miyajima, H., Imaizumi, K.
  • Journal Title: Journal of Biological Chemistry 278 Pages: 15825-15831
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] MDG1/ERdj4, an ER-resident DnaJ family member, suppresses cell death induced by ER stress. (2003)
  • Author(s): Kurisu, J., Honma, A., Miyajima, H., Kondo, S., Okumura, M., Imaizumi, K.
  • Journal Title: Genes to Cells 8 Pages: 189-202
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease. (2003)
  • Author(s): Manabe, T., Katayama, T., Sato, N., Gomi, F., Hitomi, J., Yanagita, T., Kudo, T., Honda, A., Mori, Y., Matsuzaki, S., Imaizumi, K., Mayeda, A., Tohyama, M.
  • Journal Title: Cell Death and Differentiation 10 Pages: 698-708
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Identification of Cis-acting elements for the regulation of SMN exon 7 splicing. (2002)
  • Author(s): Miyajima, H., Miyaso, H., Okumura, M., Kurisu, J., Imaizumi, K.
  • Journal Title: Journal of Biological Chemistry 277 Pages: 23271-23277
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] FAD-linked presenilin-1 mutants impede translation regulation under ER stress. (2002)
  • Author(s): Yasuda Y, Kudo T, Katayama T, Imaizumi K, Yatera M, Okochi M, Yamamori H, Matsumoto N, Kida T, Fukumori A, Okumura M, Tohyama M, Takebe M.
  • Journal Title: Biochem.Biophys.Res.Commun. 296 Pages: 313-318
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The cytosolic inclusion bodies that consist of splice variants that lack exon of the presenilin-2 gene differ obviously from Hirano bodies observed in the brain from sporadic cases of Alzheimer's disease patients. (2002)
  • Author(s): Manabe, T., Katayama, T., Sato, N., Kudo, T., Matsuzaki, S., Imaizumi, K., Tohyama, M.
  • Journal Title: Neuroscience Letters 328 Pages: 198-200
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] FAD-linked presenilin-1 mutants impede translation regulation under ER stress. (2002)
  • Author(s): Yasuda Y, Kudo T, Katayama T, Imaizumi K, Yatera M, Okochi M, Yamamori H, Matsumoto N, Kida T, Fukumori A, Okumura M, Tohyama M, Takeda M.
  • Journal Title: Biochem.Biophys.Res.Commun. 296 Pages: 313-318
  • Description: 「研究成果報告書概要(欧文)」より
• [Patent(Industrial Property Rights)] 小胞体局在転写因子OASIS及びその遺伝子の用途 (2003)
  • Inventor(s): 今泉和則, 近藤慎一, 和中明生
  • Industrial Property Rights Holder: 今泉和則, 近藤慎一, 和中明生, 科学技術振興事業団
  • Filing Date: 2003-08-05
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Miyaso, H., Okumura, M., Kondo, S., Higashide, S., Miyajima, H., Imaizumi, K.: "An intronic splicing enhancer element in SMN pre-mRNA."Journal of Biological Chemistry. 278. 15825-15831 (2003)
• [Publications] Manabe, T., Katayama, T., Sato, N., Gomi, F., Hitomi, J., Yanagita, T., Kudo, T., Honda, A., Mori, Y., Matsuzaki, S., Imaizumi, K., Mayeda, A., Tohyama, M.: "Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer's disease."Cell Death and Differentiation. 10. 698-708 (2003)
• [Publications] Katayama, T., Imaizumi, K., Yoneda, T., Taniguchi, M., Honda, A., Manabe, T., Hitomi, J., Oono, K., Baba, K., Matsuzaki, S., Takatsuji, K., Tohyama, M.: "Role of ARF4L in recycling between endosomes and the plasma membrane."Cellular and Molecular Neurobiology. 23. 991-1001 (2003)
• [Publications] Kondo, S., Yamamoto, N., Murakami, T., Okurnura, M., Mayeda, A., Imaizumi, K.: "Tra2b, SF2/ASE, and SRp30c modulate the function of an exonic splicing enhancer in exon 10 of tau pre-mRNA."Genes to Cells. (In press). (2004)
• [Publications] Imaizumi, K., Benito, A., Kiryu-Seo, S., Gonzalez, V., Inohara, N., Leiberman, A.P., Kiyama, H., Nunez, G.: "A critical role for DP5/HRK, a BH3-only Bcl-2 family member, in axotomy-induced neuronal cell death."Journal of Neuroscience. (In press). (2004)
• [Publications] Kurisu, j., Honma.A., Miyajima, H., Kondo, S., Okumura, M., Imaizumi, K.: "MDG1/ERdj4, an ER-resident DnaJ family member, suppresses cell death induced by ER stress"Genes to Cells. 8・2. 189-202 (2003)