Analysis of neuronal death-promoting mechanism of Cdk5/p25

• Project/Area Number: 19700344
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokyo Metropolitan University
• Principal Investigator: SAITO Taro Tokyo Metropolitan University, 理工学研究科, 助教 (70301413)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,720,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥420,000); Fiscal Year 2008: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2007: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: Cdk5 / 神経細胞死 / プロテインキナーゼ / 小胞体ストレス / 神経変性疾患 / ハンチントン病

Research Abstract

小胞体ストレスによる神経細胞死の過程でCdk5/p25が細胞質から核内に移行・蓄積して細胞死を促進しているとする申請者らの発見をもとに、神経細胞死におけるCdk5の役割を明らかにすることを目的として研究を行った。分子生物・生化学的研究から、Cdk5/p25の核内蓄積と細胞死促進には、p35の限定分解によるp25の生成だけでなく小胞体ストレスが必要であることが示唆された。さらに、小胞体ストレス以外の原因による神経細胞死でCdk5の役割を検討したところ、ハンチントン病の原因遺伝子産物、変異ハンチンチンの細胞内凝集体の形成をCdk5が阻害することがわかった。

Research Products

• [Journal Article] Suppression of mutant Huntingtin aggregate formation by Cdk5/p35 through the effect on microtubule stability. (2008)
  • Author(s): Kaminosono*, S., Saito*, T., Oyama, F., Ohshima, T., Asada, A., Nagai, Y., Nukina, N. and Hisanaga, S.
  • Journal Title: J Neurosci 28 Pages: 8747-8755
• [Journal Article] Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cycline-dependent kinase 5 complexes. (2008)
  • Author(s): Asada, A., Yamamoto, N., Gohda, M., Saito, T., Hayashi, N. and Hisanaga, S.
  • Journal Title: J Neurochem 106 Pages: 1325-1336
• [Journal Article] Suppression of mutant Huntingtin aggregate formation by Cdk5/p 35 through the effect on microtubule stability. (2008)
  • Author(s): Kaminosono*, S., Saito*. T, Oyama, F., Ohshima, T., Asada, A., Nagai, Y., Nukina, N. and Hisanaga, S.. (*equal contribution)
  • Journal Title: Journal of Neuroscience 28 Pages: 8747-8755
  • Peer Reviewed
• [Journal Article] Myristoylation of p39 and p35 is a determinant of cytoplasmic or nuclear localization of active cvcline-dependent kinase 5 complexes. (2008)
  • Author(s): Asada, A., Yamamoto, N., Gohda, M., Saito. T, Hayashi, N. and Hisanaga, S.
  • Journal Title: Journal of Neurochemistry 106 Pages: 1325-1336
  • Peer Reviewed
• [Journal Article] Regulation of the interaction of Disabled-1 with CIN85 by phosphorylation with Cyclin-dependent kinase 5. (2007)
  • Author(s): Sato, Y., Taoka, M., Sugiyama, N., Kubo, K., Fuchigami, T., Asada, A., Saito, T., Nakajima, K., Isobe, T. and Hisanaga, S.
  • Journal Title: Genes Cells 12 Pages: 1315-1327
• [Journal Article] Regulation of membrane association and kinase activity of Cdk5-p35 by phosphorylation of p35. (2007)
  • Author(s): Sato, K., Zhu, YS., Saito, T., Yotsumoto, K., Asada, A., Hasegawa, M. and Hisanaga, S.
  • Journal Title: Neurosci Res 85 Pages: 3071-3078
• [Journal Article] Casein kinase 2 is the major enzyme in brain that phosphorylates Ser129 of human alpha-synuclein: Implication for alpha-synucleinopathies. (2007)
  • Author(s): Ishii, A., Nonaka, T., Taniguchi, S., Saito, T., Arai, T., Mann, D., Iwatsubo, T., Hisanaga, SI., Goedert, M. and Hasegawa, M.
  • Journal Title: FEBS Lett 581 Pages: 4711-4717
• [Journal Article] Cdk5-p39 is a labile complex with the similar substrate specificity to Cdk5-p35. (2007)
  • Author(s): Yamada, M., Saito, T., Sato, Y., Kawai, Y., Sekigawa, A., Hamazumi, Y., Asada, A., Wada, M., Doi, H. and Hisanaga S.
  • Journal Title: J Neurochem 102 Pages: 1477-1487
• [Journal Article] p25/cyclin-dependent kinase 5 promotes the progression of cell death in nucleus of endoplasmic reticulum-stressed neurons. (2007)
  • Author(s): Saito, T., Konno, T., Hosokawa, T., Asada, A., Ishiguro, K. and Hisanaga, S.
  • Journal Title: J Neurochem 102 Pages: 133-140
• [Journal Article] Phosphorylation of adult type Sept5 (CDCrel-1) by cyclin-dependent kinase 5 inhibits interaction with syntaxin-1. (2007)
  • Author(s): Taniguchi, M., Taoka, M., Itakura, M., Asada, A., Saito, T., Kinoshita, M., Takahashi, M., Isobe, T. and Hisanaga, S.
  • Journal Title: J Biol Chem 282 Pages: 7869-7876
• [Journal Article] Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25by site-specific phosphorylation. (2007)
  • Author(s): Kamei, H., Saito, T., Ozawa, M., Fujita, Y., Asada, A., Bibb, J. A., Saido, T. C., Sorimachi, H. and Hisanaga, S.
  • Journal Title: Biol Chem 282 Pages: 1687-1694
• [Journal Article] Regulation of the interaction of Disabled-1 with CLN85 by phosp horylation with Cyclin-dependent kinase 5 (2007)
  • Author(s): Sato, Y., Taoka, M., Sugiyama, N., Kubo, K., Fuchigsmi, T., Asada, A., Saito, T., Nakajima, K., Isobe, T. and Hisanaga, S.
  • Journal Title: Gense to Cells 12 Pages: 1315-1327
  • Peer Reviewed
• [Journal Article] Regulation of membrane association and kinase activity of Cdk5-p35 by phosphorylation of p35 (2007)
  • Author(s): Sato, K., Zhu, YS., Saito, T., Yotsumoto, K., Asada, A., Hasegawa, M, and Hisanaga, S.
  • Journal Title: Journal of Neuroscience Research 85 Pages: 3071-3078
  • Peer Reviewed
• [Journal Article] Casein kinase 2 is the major enzyme in brain that phosthorylates Ser129 of human alpha-synuclein:lmplication for alpha-synuc leinopathies (2007)
  • Author(s): Ishii, A., Nonaka, T., Taniguchi, S., Saito, T., Arai, T., Mann, D., Iwatsubo, T., Hisanaga, SI., Goedert, M. And Hasegawa, M.
  • Journal Title: FEBS Lettes 581 Pages: 4711-4717
  • Peer Reviewed
• [Journal Article] Cdk5-p35 is a labile complex with the similar substrate specificity to Cdk5-p35 (2007)
  • Author(s): Yamada, M., Saito, T., Sato, Y., Kawai, Y., Sekigawa, A., Hamazumi, Y., Asada, A., Wada, M., Doi, H. and Hisanaga S.
  • Journal Title: Journal of Neurochemistry 102 Pages: 1477-1478
  • Peer Reviewed
• [Journal Article] p25/cyclin-dependent kinase 5 pronmotes the progression of cell death in nucleus of endoplasmic reticulum-stressed neurons (2007)
  • Author(s): Saito, T., Konno, T., Hosokawa, T., Asads, A., Ishiguro, K. and Hisanaga, S.
  • Journal Title: Journal of Neurochemistry 102 Pages: 133-140
  • Peer Reviewed
• [Journal Article] Phosphorylation of adult type Sept5(CDCrel-1)by cyclin-depend ent kinase 5 inhibits interaction with symtaxin-1 (2007)
  • Author(s): Taniguchi, M., Taoka, M., Itakura, M., Asada, A., Saito, T., Kinoshita, M., Takahashi, M., Isobe, T. and Hisanaga, S.
  • Journal Title: Journal of Biologial Chemistry 282 Pages: 7869-7876
  • Peer Reviewed
• [Journal Article] Suppression of calpain-dependent cleavage of the CDK5 activator p35 to p25 by site-specific phosphorylation (2007)
  • Author(s): Kamei, H., Saito, T., Ozawa, M., Fujita, Y., Asada, A., Bibb, J.A., Saido, T.C., Sorimachi, H. and Hisanaga, S.
  • Journal Title: Journal of Biologial Chemistry 282 Pages: 1687-1694
  • Peer Reviewed
• [Presentation] 後シナプス領域におけるCdk5とCaMKIIの相互作用 (2008)
  • Author(s): 細川智永、斎藤太郎、浅田明子、久永眞市
  • Organizer: 第51回日本神経化学会大会
  • Place of Presentation: 富山
• [Presentation] Cdk5/p35によるハンチントン病原因タンパク質ハンチンチンの凝集阻害 (2008)
  • Author(s): 斉藤太郎、上之薗紗有子、小山文隆、浅田明子、永井義隆、貫名信行、久永眞市
  • Organizer: 第31回日本神経科学大会
  • Place of Presentation: 東京
• [Presentation] 神経細胞死におけるp25/Cdk5の核移行 (2007)
  • Author(s): 斎藤太郎、遠藤良、浅田明子、久永真市
  • Organizer: 第50回日本神経化学会大会
  • Place of Presentation: 横浜
• [Presentation] Regulation of the interaction of Dab1 with CIN85 by phosphorylation with Cyclin-dependent kinase 5. (2007)
  • Author(s): Sato, Y., Taoka, M., Sugiyama, N., Kubo, K., Fuchigami, T., Asada, A., Saito, T., Nakajima, K., Isobe, T., Hisanaga, S.
  • Organizer: 細胞生物学会
  • Place of Presentation: 福岡
• [Presentation] パーキンソン病モデル神経細胞におけるCdk5活性化サブユニットp35の分解制御と細胞死 (2007)
  • Author(s): 遠藤良、斎藤太郎、浅田明子、久永眞市
  • Organizer: 病態と治療におけるプロテアーゼとインヒビター学会
  • Place of Presentation: 大阪
• [Presentation] 膜結合に依存したCdk5活性化サブユニットp35とp39の分解制御機構の解析 (2007)
  • Author(s): 嶺岸正治、浅田明子、宮内伸也、渕上孝裕、斎藤太郎、久永眞市
  • Organizer: 病態と治療におけるプロテアーゼとインヒビター学会
  • Place of Presentation: 大阪
• [Presentation] MPP+又は6-OHDAによるCdk5/p35の分解制御と細胞死 (2007)
  • Author(s): 遠藤良、斎藤太郎、浅田明子、久永眞市
  • Organizer: 第50回日本神経化学会大会
  • Place of Presentation: 横浜
• [Presentation] Cdk5/p35による変異型ハンチンチンの凝集抑制 (2007)
  • Author(s): 上之薗紗有子,斉藤太郎,小山文隆,浅田明子,永井義隆,貫名信行,久永眞市
  • Organizer: 第50回日本神経化学会大会
  • Place of Presentation: 横浜
• [Presentation] Regulation of the membrane association and kinase activity of Cdk5-p35 by phosphorylation of p35. (2007)
  • Author(s): Sato, K., Zhu, Y-S., Saito, T., Yotsumoto, K., Asada, A., Hasegawa, M., Hisanaga, S.
  • Organizer: 第50回日本神経化学会大会
  • Place of Presentation: 横浜
• [Presentation] Deregulation of p35 Cdk5 activator metabolisms in MPP+-induced neuronal cell death. (2007)
  • Author(s): Endo, R., Saito, T., Asada, A., Hisanaga, S.
  • Organizer: 第37回北米神経科学会
  • Place of Presentation: サンディエゴ
• [Presentation] Crosstalk between Cdk5 and CaMKII in the postsynaptic region. (2007)
  • Author(s): Hosokawa, T., Saito, T., Asada, A., Hisanaga, S.
  • Organizer: 第37回北米神経科学会
  • Place of Presentation: サンディエゴ
• [Presentation] p25/cyclin-dependent kinase 5 promotes the progression of cell death in nucleus of endoplasmic reticulum-stressed neurons. (2007)
  • Author(s): Saito, T., Konno, T., Hosokawa, T., Asada, A., Ishiguro, K., Hisanaga, S.
  • Organizer: 第37回北米神経科学会
  • Place of Presentation: サンディエゴ
• [Presentation] Inhibition of mutant huntingtin aggregate formation by Cdk5/p35. (2007)
  • Author(s): Kaminosono, S., Saito, T., Oyama, F., Asada, A., Nukina, N., Hisanaga, S.
  • Organizer: 第37回北米神経科学会
  • Place of Presentation: サンディエゴ
• [Presentation] Proteolysis of Cdk5 activators p35 and p39 on membranes. (2007)
  • Author(s): Minegishi, S., Asada, A., Miyauchi, S., Fuchigami, T., Saito, T., Ishiguro, K., Hisanaga, S.
  • Organizer: 第37回北米神経科学会
  • Place of Presentation: サンディエゴ
• [Presentation] Crosstalk between Cdk5 and CaMKII in the postsynaptic region. (2007)
  • Author(s): 細川智永、斉藤太郎、浅田明子、久永真市
  • Organizer: 第30回分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] AATYKキナーゼによる神経特異的Cdk、Cdk5の活性化 (2007)
  • Author(s): 堤弘次、浅田明子、斉藤太郎、久永眞市
  • Organizer: 第30回日本分子生物学会
  • Place of Presentation: 横浜
• [Presentation] p35/Cdk5とp39/Cdk5の細胞内局在に及ぼすCdk5キナーゼ活性の影響 (2007)
  • Author(s): 浅田明子、小澤美来、斉藤太郎、久永真市
  • Organizer: 第30回分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] 神経細胞の生死を決めるCdk5の膜結合と核移行 (2007)
  • Author(s): 久永真市、浅田明子、斉藤太郎
  • Organizer: 第30回分子生物学会ワークショップ
  • Place of Presentation: 横浜
• [Presentation] Cdk5活性化サブユニットp35とp39は膜上で選択的に分解されている (2007)
  • Author(s): 嶺岸正治、浅田明子、渕上孝裕、宮内伸也、斎藤太郎、久永眞市
  • Organizer: 第30回分子生物学会年会
  • Place of Presentation: 横浜
• [Presentation] Dephosphorylation of Cdk5-phosphorylated FTDP-17 mutant tau. (2007)
  • Author(s): Yotsumoto, K., Sakaue, F., Oikawa, T., Ishiguro, K., Saito, T., Asada, A., Hasegawa, M., Hisanaga, S.
  • Organizer: 認知症学会
  • Place of Presentation: 大阪
• [Presentation] p25/cyclin-dependent kinase 5 promotes the rpogression of cell death in nucleus of endoplasmic r eticulum-stressed neurons (2007)
  • Author(s): Taro Saito, Tsunetada Konno, Tomohisa Hosokawa, Akiko Asada, Koichilshiguro and Shin-ichi Hisanaga
  • Organizer: 第37回北米神経科学会
  • Place of Presentation: サンディエゴ