Identification of therapeutic targets by genetic studies of neurodegeneration signal

• Project/Area Number: 17025010
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: MIURA Masayuki The University of Tokyo, 大学院・薬学系研究科, 教授 (50202338)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥101,500,000 (Direct Cost: ¥101,500,000); Fiscal Year 2009: ¥20,700,000 (Direct Cost: ¥20,700,000); Fiscal Year 2008: ¥20,400,000 (Direct Cost: ¥20,400,000); Fiscal Year 2007: ¥20,400,000 (Direct Cost: ¥20,400,000); Fiscal Year 2006: ¥20,400,000 (Direct Cost: ¥20,400,000); Fiscal Year 2005: ¥19,600,000 (Direct Cost: ¥19,600,000)
• Keywords: モデル生物 / ショウジョウバエ / 細胞死 / 神経変性 / プロテアソーム / ポリグルタミン病 / 変性蛋白質 / 遺伝学 / IAPファミリー / カスパーゼ / bcl-2 / drob-1 / RNA干渉法

Research Abstract

The ubiquitin-proteasome system, which contributes to protein quality control by degrading unfolded or misfolded proteins, is closely related to the etiology of neurodegenerative disorders. The 26S proteasome is composed of one, proteolytically active, core particle (alias 20S proteasome) and one or two 19S regulatory particles subdivided into lid and base subcomplexes. In a genetic gain-of-function screen, we identified one of the lid subunits as a suppressor of expanded polyglutamine-induced neurodegenerative phenotypes in a Drosophila disease model. Our results suggest that an age-related reduction in 26S proteasome activity is the key factor of the increased risk for late-onset of neurodegeneration, and implicate that keeping the amount of the 26S proteasome by providing an overexpressed lid subunit will provide a way to delay the onset of neurodegeneration in vivo.

Research Products

• [Journal Article] Temporal regulation of Drosophila IAP determines the dual functions of caspases in sensory organ development. (2009)
  • Author(s): Koto, A., Kuranaga, E., Miura, M.
  • Journal Title: J. Cell Biol. 187 Pages: 219-321
• [Journal Article] Caspase-9 activation revealed by Semaphorin 7A cleavage is independent of apoptosis in the aged olfactory bulb. (2009)
  • Author(s): Ohsawa, S., Hamada, S., Asou, H., Kuida, K., Uchiyama, Y., Yoshida, H., Miura, M.
  • Journal Title: J. Neurosci. 29 Pages: 11385-11392
• [Journal Article] Genetic evidence linking age-dependent attenuation of the 26S proteasome with aging process. (2009)
  • Author(s): Tonoki, A., Kuranaga, E., Tomioka, T., Hamazaki, J., Murata, S., Tanaka, K., Miura, M.
  • Journal Title: Mol Cell Biol. 29 Pages: 1095-1106
• [Journal Article] Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila (2009)
  • Author(s): Igaki T, Pastor-Pareja JC, Aonuma H, Miura M, Xu T
  • Journal Title: Developmental cell 16 Pages: 458-65
  • Peer Reviewed
• [Journal Article] Caspase-9 activation revealed by semaphorin 7A cleavage is independent of apoptosis in the aged olfactory bulb (2009)
  • Author(s): Ohsawa S, Hamada S, Asou H, Kuida K, Uchiyama Y, Yoshida H, Miura M
  • Journal Title: The Journal of neuroscience : the official journal of the Society for Neuroscience 29 Pages: 11385-92
  • Peer Reviewed
• [Journal Article] p38 MAPK-dependent phagocytic encapsulation confers infection tolerance in Drosophila (2009)
  • Author(s): Shinzawa N, Nelson B, Aonuma H, Okado K, Fukumoto S, Miura M, Kanuka H
  • Journal Title: Cell host & microbe 6 Pages: 244-52
  • Peer Reviewed
• [Journal Article] Temporal regulation of Drosophila IAP1 determines caspase functions in sensory organ development (2009)
  • Author(s): Koto A, Kuranaga E, Miura M
  • Journal Title: The Journal of cell biology 187 Pages: 219-31
  • Peer Reviewed
• [Journal Article] Intrinsic tumor suppression and epithelial maintenance by endocytic activation of Eiger/TNF signaling in Drosophila (2009)
  • Author(s): Igaki, T., Pastor-Pareja, J. C., Aonuma, H., Miura, M., and Xu, T.
  • Journal Title: Dev. Cell 16 Pages: 458-465
  • Peer Reviewed
• [Journal Article] Genetic evidence linking age-dependent attenuation of the 26S pro easome with aging process (2009)
  • Author(s): Tonoki, A., Kuranaga, E., T omioka, T., Hamazaki, J., Murata, S., Tanaka, K., and Miura, M.
  • Journal Title: Mol. Cell Biol. 29 Pages: 1095-1106
  • Peer Reviewed
• [Journal Article] Caspase-mediated changes in Histone H1 in early apoptosis: prolonged caspase activation in developing olfactory sensory neurons. (2008)
  • Author(s): Ohsawa, S., Hamada, S., Yoshida, H., Miura, M.
  • Journal Title: Cell Death Diff. 15 Pages: 1429-1439
• [Journal Article] RNA-binding protein Hoip accelerates polyQ-induced neurodegener ation in Drosophila. (2008)
  • Author(s): Murata, T., Suzuki, E., Ito, S., Sawatsubashi, S., Zhao, Y., Yamagata, K., Tanabe, M., Fujiyama, S., Kimura, S., Ueda, T., Matsukawa, H Kouzmenko, A., Furutani, T., Kuranaga, E., Miura, M., Takeyama, K., and Kato, S.
  • Journal Title: Biosci. Biotechnol. Biochem. 72 Pages: 2255-2261
  • Peer Reviewed
• [Journal Article] A Drosophila orphan GPCR BOSS functions as a glucose-respondi ng receptor : loss of boss causes abnormal sugar and lipid metabolism (2008)
  • Author(s): Kohyama-Koganeya, A., Ki m, Y J., Miura, M., and Hirabavashi, Y.
  • Journal Title: PNAS 105 Pages: 15328-15333
  • Peer Reviewed
• [Journal Article] Novel antibody to human BASPl labels apoptotic cells post-caspase activation (2008)
  • Author(s): Ohsawa. S., Watanabe, T., Katada, T., Nishina, H., and Miura, M.
  • Journal Title: BBRC 371 Pages: 639-643
  • Peer Reviewed
• [Journal Article] Caspase-mediated changes in Histone Hi in early apoptosis : prolonged caspase activation in developing olfactory sensory nenrnns (2008)
  • Author(s): Ohsawa, S., Hamada, S., Yo shida, H., and Miura, M.
  • Journal Title: Cell Death Diff. 15 Pages: 1429-1439
  • Peer Reviewed
• [Journal Article] Evolution of mitochondrial cell death pathway: Proapoptotic role of HtrA2/Omi in Drosophila. (2007)
  • Author(s): Igaki, T., Suzuki, Y., Tokushige, N., Aonuma, H., Takahashi, R., and Miura, M
  • Journal Title: BBRC 356 Pages: 993-997
  • Peer Reviewed
• [Journal Article] Local initiation of caspase activation in Drosophila salivary gland programmed cell death in vivo. (2007)
  • Author(s): Takemoto, K., Kuranaga, E., Tonoki, A., Nagai, T., Miyawaki, A., and Miura, M
  • Journal Title: Proc. Natl. Acad. Sci. USA 104 Pages: 13367-13372
  • Peer Reviewed
• [Journal Article] Tumor suppressor CYLD regulates JNK-Induced cell death in Drosophila. (2007)
  • Author(s): Xue, L., Igaki, T., Kuranaga, E., Kanda, H., Miura, M., and Xu, T
  • Journal Title: Dev. Cell 13 Pages: 446-454
  • Peer Reviewed
• [Journal Article] DIAP2 functions as a mechanism-based regulator of drICE that contributes to the caspase activity threshold in living cells. (2007)
  • Author(s): Ribeiro, P.S., Kuranaga, E., Tenev, T., Leulier, F., Miura, M., Meier, P
  • Journal Title: J. Cell Biol. 179 Pages: 1467-1480
  • Peer Reviewed
• [Journal Article] Drosophila IKK-related kinase regulates nonapoptotic function of caspases via degradation of IAPs. (2006)
  • Author(s): Kuranaga, E., Kanuka, H., Tonoki, A., Takemoto, K., Tomioka, T., Kobayashi, M., Hayashi, S., Miura, M.
  • Journal Title: Cell 126 Pages: 583-596
• [Journal Article] Caspase-mediated changes in Sir2α during apoptosis. (2006)
  • Author(s): Ohsawa, S., Miura, M
  • Journal Title: FEBS Lett. 580 Pages: 5875-5879
• [Journal Article] Dronc coordinates cell death and compensatory proliferation. (2006)
  • Author(s): Kondo, S., Senoo-Matsuda, N., Hiromi, Y., Miura, M
  • Journal Title: Mol. Cell. Biol. 26 Pages: 7258-7268
• [Journal Article] Drosophila IKK-related kinase regulates nonapoptotic function of caspases via degradation of IAPs. (2006)
  • Author(s): Kuranaga, E., Kanuka, H., Tonoki, A., Takemoto, K., Tomioka, T., Kobayashi, M., Hayashi, S., Miura, M
  • Journal Title: Cell 126 Pages: 583-596
• [Journal Article] IKKε regulates F actin assembly and interacts with Drosophila IAP1 in cellular morphogenesis. (2006)
  • Author(s): Oshima, K., Takeda, M., Kuranaga, E., Ueda, R., Aigaki, T., Miura, M., Hayashi, S
  • Journal Title: Curr. Biol. 16 Pages: 1531-1537
• [Journal Article] Bax-like protein Drob-1 protects neurons from expanded polyglutamine-induced toxicity in Drosophila. (2005)
  • Author(s): Senoo-Matsuda, N., Igaki, T., Miura, M.
  • Journal Title: EMBO J. 24 Pages: 2700-2713
• [Journal Article] Gain-of-function screen identifies a role of the Sec61αtranslocon in Drosophila postmitotic neurotoxicity. (2005)
  • Author(s): Kanuka, H., Hiratou, T., Igaki, T., Kanda, H., Kuranaga, E., Sawamoto, K., Aigaki, T., Okano, H., Miura, M.
  • Journal Title: BBA 1726 Pages: 225-237
• [Journal Article] Role of 14-3-3γ in FE65-dependent gene transactivation mediated by the APP cytoplasmic fragment. (2005)
  • Author(s): Sumioka, A., Nagaishi, S., Yoshida, T., Lin, A., Miura, M., Suzuki, T.
  • Journal Title: J.Biol.Chem. 280 Pages: 42364-42374
• [Journal Article] Gain-of-function screen identifies a role of the Sec6lα translocon in Drosophila postmitotic neurotoxicity. (2005)
  • Author(s): Kanuka, H., Hiratou, T., Igaki, T., Kanda, H., Kuranaga, E., Sawamoto, K., Aigaki, T., Okano, H., Miura, M.
  • Journal Title: BBA 1726 Pages: 225-237
• [Journal Article] Drosophila caspase transduces Shaggy/GSK-3β kinase activity in neural precuorsor development. (2005)
  • Author(s): Kanuka, H., Kuranaga, E., Takemoto, K., Hiratou, T., Okano, H., Miura, M.
  • Journal Title: EMBO J. 24 Pages: 3793-3806
• [Journal Article] Targeted expression of anti-apoptotic protein p35 in oligodendrocytes reduces delayed demyelination and functional impairment after spinal cord injury. (2005)
  • Author(s): Tamura, M., Nakamura, M., Ogawa, Y., Toyama, Y., Miura, M., Okano, H.
  • Journal Title: Glia 51 Pages: 312-321
• [Journal Article] Isolation of gene sets affected specifically by polyglutamine expression : implication of the TOR signaling pathway in neurodegeneraton. (2005)
  • Author(s): Nelson, B., Nishimura, S., Kanuka, H., Kuranaga, E., Inoue, M., Hori, G., Nakahara, H., Miura, M.
  • Journal Title: Cell Death Diff. 12 Pages: 1115-1123
• [Presentation] Live-imaging analysis of apoptosis in vivo by using transgenic mice expressing a genetically encoded reporter for caspase activation (2009)
  • Author(s): Shinotsuka, N., Yamaguchi, Y., Takemoto, K., Miura, M
  • Organizer: 第32回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2009-12-09
• [Presentation] Birth and death of the sensory organ precursor cells : a role of programmed cell death in Drosophila sensory organ development (2009)
  • Author(s): 三浦正幸
  • Organizer: The 4th International Workshop on Cell Regulations in Division and Arrest
  • Place of Presentation: Okinawa, Japan
  • Year and Date: 2009-11-29
• [Presentation] Live-imaging analysis of apoptosis and caspase activation in mornhoefenesis (2009)
  • Author(s): Yamaguchi, Y., Shinotsuka N.Nonomura, K., Miura, M
  • Organizer: he 4th International Workshop on Cell Regulations in Division and Arrest
  • Place of Presentation: Okinawa, Japan
  • Year and Date: 2009-11-29
• [Presentation] Temporal regulation of Drosophila IAP1 determines the dual functions of caspases in the sensory organ development (2009)
  • Author(s): 古藤日子, 倉永英里奈, 三浦正幸
  • Organizer: 21^<st> European Drosophila Research Conference
  • Place of Presentation: Nice, France
  • Year and Date: 2009-11-18
• [Presentation] IAPタンパク質の時空間的な発現変化はカスパーゼの非細胞死機能を制御する (2009)
  • Author(s): 古藤日子、倉永英里奈、三浦正幸
  • Organizer: 第82回日本生化学会大会シンポジウム
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-21
• [Presentation] Caspase-mediated apoptosis is dispensable for the control of cell number in the early developing brain (2009)
  • Author(s): Nonomura, K., Yamaguchi, Y.Yoshida, H., Miura, M
  • Organizer: Cold Spring Harbor Laboratory Meeting, Cell Death
  • Place of Presentation: New York, USA
  • Year and Date: 2009-10-06
• [Presentation] 生体におけるカスパーゼ活性化ダイナミクス (2009)
  • Author(s): 三浦正幸
  • Organizer: 日本アポトーシス研究会学術集会ワークショップ
  • Place of Presentation: 長崎
  • Year and Date: 2009-08-01
• [Presentation] A Role of Programmed Cell Death in Drosophila Bristle Pattern Formation : Appearance and Elimination of the Ectopic Sensory Organ Precursor Cells (2009)
  • Author(s): 古藤日子, 倉永英里奈, 三浦正幸
  • Organizer: The 9th Japanese Drosophila Research Conference
  • Place of Presentation: 掛川
  • Year and Date: 2009-07-06
• [Presentation] 26S proteasome determines the onset and severity of age-related neurodegenerative disease (2009)
  • Author(s): 三浦正幸
  • Organizer: International Symposium on Autophagy and Cell Death
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2009-07-04
• [Presentation] Programmed Cell Death Functions in Drosophila Bristle Pattern Formation (2009)
  • Author(s): 古藤日子, 倉永英里奈, 三浦正幸
  • Organizer: 第42回日本発生生物学会大会
  • Place of Presentation: 新潟
  • Year and Date: 2009-05-28
• [Presentation] Is apoptosis required for the regulation of cell number in the early developing brain? -Quantitative analysis of morphological abnormalities in the brain of mice deficient for apoptosis signaling (2009)
  • Author(s): Nonomura, K., Yamaguchi, Y.Yoshida, H., Miura, M
  • Organizer: 第42回日本発生生物学会大会
  • Place of Presentation: 新潟
  • Year and Date: 2009-05-28
• [Presentation] An effective and convenient method to express transgene by the combination of in utero electroporation and the Tol2 transposon system ; inducible or cell-type specific expression in glia (2009)
  • Author(s): Yoshida, A., Yamaguchi, Y., Nonomura, K., Kawakami, K., Takahashi, Y., Miura, M
  • Organizer: 日本発生生物学会 第42回大会
  • Place of Presentation: 新潟
  • Year and Date: 2009-05-28
• [Presentation] ショウジョウバエを用いたポリグルタミン病へのアプローチ (2009)
  • Author(s): 倉永英里奈、殿城亜矢子、三浦正幸
  • Organizer: 第50回日本神経学会シンポジウム
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-22
• [Presentation] In vivo dynamics of cell death signaling during animal develo pment (2008)
  • Author(s): Miura, M.
  • Organizer: Symposium in BMB 2008
  • Place of Presentation: Kobe, Japan.
  • Year and Date: 2008-12-09
• [Presentation] In vivo dynamics of cell death signaling in the Drosophila se nsory organ development (2008)
  • Author(s): Miura, M.
  • Organizer: International Cell Death Society Symposium
  • Place of Presentation: Shanghai, China
  • Year and Date: 2008-06-07
• [Presentation] In vivo imaging and physiological roles of cell death signaling during development. (2008)
  • Author(s): Miura, M.
  • Organizer: The 15th Takeda Science Foundation Symposium on Bioscience
  • Place of Presentation: Tokyo, Japan
• [Presentation] Involvement of the 26S proteasome in the age-related neurodegenerative diseases. (2008)
  • Author(s): Tonoki, A., Kuranaga, E., Tomioka, T., Hamazaki, J., Murata, S., Tanaka, K., Miura, M.
  • Organizer: BMB 2008 Symposium
  • Place of Presentation: Kobe, Japan
• [Presentation] Involvement of the 26S proteasome in Drosophila model of age-related neurodegenerative disease. (2008)
  • Author(s): Miura, M.
  • Organizer: The 31st Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: Tokyo, Japan
• [Presentation] Non-apoptotic function of caspase signaling in Drosophila. (2007)
  • Author(s): Miura, M.
  • Organizer: Keystone Symposium
  • Place of Presentation: Monterey, California, USA
• [Presentation] Novel function of caspase activation signal in neural development. (2007)
  • Author(s): Miura, M.
  • Organizer: Symposium in BMB 2007
  • Place of Presentation: Yokohama, Japan.
• [Remarks]
  • URL: http://www.f.u-tokyo.ac.jp/~genetics/index.html
• [Remarks]
  • URL: http://www.f.u-tokyo.ac.jp/~genetics/index.html
• [Remarks]
  • URL: http://www.f.u-tokyo.ac.jp/~genetics/index.html
• [Remarks]
  • URL: http://www.f.u-tokyo.ac.jp/~genetics/index.html
• [Patent(Industrial Property Rights)] 生体刺激存在下でのmRNAのフレームシフトを利用した蛋白質の発現方法 (2010)
  • Inventor(s): 三浦正幸、岩脇隆夫
  • Industrial Property Rights Holder: 理化学研究所
  • Acquisition Date: 2010-01-29