Molecular mechanism of the qualify control of proteins
Project/Area Number |
17028032
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Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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Allocation Type | Single-year Grants |
Review Section |
Biological Sciences
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Research Institution | Osaka University |
Principal Investigator |
TOHYAMA Masaya Osaka University, Graduate school of medicine, Professor (40028593)
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Co-Investigator(Kenkyū-buntansha) |
MORI Yasutake Osaka university, Graduate school of medicine, Associate Professor (00343252)
INOUE Kiyoshi Osaka university, Graduate school of medicine, Assistant Professor (20342719)
MATSUZAKI Shinsuke Osaka university, Graduate school of medicine, Assistant Professor (60403193)
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Project Period (FY) |
2002 – 2006
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Project Status |
Completed (Fiscal Year 2006)
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Budget Amount *help |
¥49,200,000 (Direct Cost: ¥49,200,000)
Fiscal Year 2006: ¥24,600,000 (Direct Cost: ¥24,600,000)
Fiscal Year 2005: ¥24,600,000 (Direct Cost: ¥24,600,000)
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Keywords | endoplasmic reticulume (ER) / ER stress / caspase-4 / Alzheimer's disease (AD) / HMGAla / presenilin-2 splice valiants (PS2V) / cell death / therapy / アルツハイマー病 / 蛋白質品質管理機構 / カスペース4 / カスペース3 / カスペース9 / チトクロームC / プレセニリン1変異体 / 神経細胞死 / プレセニリン2スプライシング変種 |
Research Abstract |
In this research, we examined the involvement of to the endoplasmic reticulum (ER) stress in both familial and sporadic Alzheimer's disease (AD). As the resulrts, we showed that familial AD-linked presenilin-1 (PS1) mutation induced the fragility to the ER stress and that one of the presenilin-2 (PS2) splice valiants (PS2V), which were observed in the sporadic AD patient brains, also caused the fragility to the ER stress. Further studies elucidated that hydroxy radicals caused by hypoxia, metals, etc. induced HMGAla protein resulting in the aberrant splicing variant (PS2V). These results suggest the inhibition of HMGAla protein as the new therapy for sporadic AD. Next, we investigated the apoptosis pathway under the ER stress and found that caspase-4 mediates ER stress induced- and β-amyloid induced-apoptotic signaling in human cells. These results suggest the involvement of ER stress and caspase-4 in the cell death observed in AD. Thus, we studied the activation of caspase-4 in the familial AD-linked PS1 mutation (ΔE9). Cleavage of caspase-4 under ER stress was enhanced by the overexpression of the familial AD-linked mutation (ΔE9), showing that caspase-4 is a key caspase involved in the apoptotic signaling of AD. We also showed that the overexpression of caspase-4 induced cleavage of caspase-9 and caspase-3 without releasing cytochrome-c from the mitochondria. These results also suggest that the regulation of activated caspase-4 should be one of the new therapies for AD.
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Report
(3 results)
Research Products
(117 results)
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[Journal Article] A novel DISC1-interacting partner DISC1-Binding Zincfinger protein: implication in the modulation of )DISC1-dependent neurite outgrowth2007
Author(s)
Hattori T, Baba K, Matsuzaki S, Honda A, Miyoshi K, Inoue K, Taniguchi M, Hashimoto H, Shintani N, Baba A, Shimizu S, Yukioka F, Kumamoto N, Yamaguchi A, Tohyama M, Katayama T
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Journal Title
Molecular Psychiatry; 12(4)
Pages: 398-407
Description
「研究成果報告書概要(和文)」より
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Peer Reviewed
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[Journal Article] A novel DISCI-interacting partner DISCI-Binding Zincfinger protein : implication in the modulation of DISC1-dependent neurite outgrowth2007
Author(s)
Hattori T, Baba K, Matsuzaki S, Honda A, Miyoshi K, Inoue K, Taniguchi M, Hashimoto H, Shintani N, Baba A, Shimizu S, Yukioka F, KumamotoN, Yamaguchi A, Tohyama M, Katayama T
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Journal Title
Molecular Psychiatry 12(4)
Pages: 398-407
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] A secreted type of beta 1, 6 N-acetylglucosaminyltransferase V (GnT-V), a novel angiogenesis inducer, is regulated by gamma-secretase.2006
Author(s)
Nakahara s, Saito T, Kondo N, Moriwaki K, Noda K, Ihara S, Takahashi M, Ide Y, Gu J, Inohara H, Katayama T, Tohyama M, Kubo T, Taniguchi N, Miyoshi E.
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Journal Title
FASEB J. 20(14)
Pages: 2451-2459
Description
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[Journal Article] Altered localization of amyloid precursor protein under endoplasmic reticulum stress.2006
Author(s)
Kudo T, Okumura M, Imaizumi K, Araki W, Morihara T, Tanimukai H, Kamagata E, Tabuchi N, Kimura R, Kanayama D, Fukumori A, Tagami S, Okochi M, Kubo M, Tanii H, Tohyama M, Tabira T, Takeda M.
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Journal Title
Biochem Biophys Res Commun. 344(2)
Pages: 525-530
Description
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[Journal Article] A secreted type of beta1,6 N-acetylglucosaminyltransferase V (GnT-V), a novel angiogenesis inducer, is regulated by gamma-secretase.2006
Author(s)
Nakahara S, Saito T, Kondo N, Moriwaki K, Noda K, Ihara S, Takahashi M, Ide Y, Gu J, Inohara H, Katayama T, Tohyama M, Kubo T, Taniguchi N, Miyoshi E.
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Journal Title
FASEB J. 20(14)
Pages: 2451-9
Description
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[Journal Article] Altered localization of amyloid precursor protein under endoplasmic reticulum stress2006
Author(s)
Kudo T, Okumura M, Imaizumi K, Araki W, Morihara T, Tanimukai H, Kamagata E, Tabuchi N, Kimura R, Kanayama D, Fukumori A, Tagami S, Okochi M, Kubo M, Tanii H, Tohyama M, Tabira T, Takeda M.
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Journal Title
Biochem Biophys Res Commun. 344(2)
Pages: 525-30
Description
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[Journal Article] A secreted type of betal,6 N-acetylglucosaminyltransferase V (GnT-V), a novel angiogenesis inducer, is regulated by gamma-secretase.2006
Author(s)
Nakahara S, Saito T, Kondo N, Moriwaki K, Noda K, Ihara S, Takahashi M, Ide Y, Gu J, Inohara H, Katayama T, Tohyama M, Kubo T, Taniguchi N, Miyoshi E
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Journal Title
FASEB J. 20(14)
Pages: 2451-2459
Related Report
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[Journal Article] Altered localization of amyloid precursor protein under endoplasmic reticulum stress.2006
Author(s)
Kudo T, Okumura M, Imaizumi K, Araki W, Morihara T, Tanimukai H, Kamagata E, Tabuchi N, Kimura R, Kanayama D, Fukumori A, Tagami S, Okochi M, Kubo M, Tanii H, Tohyama M, Tabira T, Takeda M
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Journal Title
Biochem Biophys Res Commun. 344(2)
Pages: 525-530
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[Journal Article] Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death.2004
Author(s)
Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, lmaizumi K, Tsujimoto Y, Tohyama M.
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Journal Title
J Cell Biol. 165(3)
Pages: 347-56
Description
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[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.
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Journal Title
Cell Mol Neurobiol.
Pages: 137-47
Description
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[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.
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Journal Title
Neurochem Int. 45(5)
Pages: 765-72
Description
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[Journal Article] Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-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.
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Journal Title
J Cell Biol. 165(3)
Pages: 347-56
Description
「研究成果報告書概要(欧文)」より
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[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.
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Journal Title
Cell Mol Neurobiol. 24(1)
Pages: 137-47
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[Journal Article] Disrupted-In-Schizophrenia 1, a candidate gene for schizophrenia, participates in neurite outgrowth.2003
Author(s)
Miyoshi K, Honda A, Baba K, Taniguchi M, Oono K, Fujita T, Kuroda S, Katayama T, Tohyama M.
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Journal Title
Mol Psychiatry. 8(7)
Pages: 685-94
Description
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[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.
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Journal Title
Cell Death Differ. 10(6)
Pages: 698-708
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[Journal Article] Disrupted-In-Schizophrenia 1, acandidate gene for schizophrenia, participates in neurite outgrowth.2003
Author(s)
Miyoshi K, Honda A, Baba K, Taniguchi M, Oono K, Fujita T, Kuroda S, Katayama T, Tohyama M.
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Journal Title
Mol Psychiatry. 8(7)
Pages: 685-94
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Induced HMGAla 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.
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Journal Title
Cell Death Differ. 10(6)
Pages: 698-708
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[Journal Article] FAD-linked presenilin-1 mutants impede translation regulation under ER stress.2002
Author(s)
Yasuda Y, Kudo T, Katayama T, lmaizumi K, Yatera M, Okochi M, Yamamori H, Matsumoto N, Kida T, Fukumori A, Okumura M, Tohyama M, Takeda M.
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Journal Title
Biochem Biophys Res Commun. 296(2)
Pages: 313-8
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[Journal Article] Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia.2002
Author(s)
Suzuki Y, Miura H, Tanemura A, Kobayashi K, Kondoh G, Sano S, OZawa K, Inui S, Nakata A, Takagi T, Tohyama M, Yoshikawa K, Itami S.
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Journal Title
FEBS Lett. 521(1-3)
Pages: 67-71
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[Journal Article] Expression of mitochondrial tricarboxylate carrier TCC mRNA and protein in the rat brain.2002
Author(s)
Miyake S, Yamashita T, Taniguchi M, Tamatani M, Sato K, Kawai Y, Senba E, Mitsuda N, Hori O, Yamaguchi A, Tohyama M.
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Journal Title
Brain Res Mol Brain Res. 100(1-2)
Pages: 67-73
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[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.
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Journal Title
Biochem Biophys Res Commun. 296(2)
Pages: 313-8
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Targeted disruption of LIG-1 gene results in psoriasiform epidermal hyperplasia.2002
Author(s)
Suzuki Y, Miura H, Tanemura A, Kobayashi K, Kondoh G, Sano S, Ozawa K, Inui S, Nakata A, Takagi T, Tohyama M, Yoshikawa K, Itami S.
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Journal Title
FEBS Lett. 521(1-3)
Pages: 67-71
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