Analysis of the neuropathological mechanism by using calpain mutant mice

• Project/Area Number: 22700379
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: The Institute of Physical and Chemical Research
• Principal Investigator: TAKANO Jiro 独立行政法人理化学研究所, 神経蛋白制御研究チーム, 研究員 (60415213)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: カルパイン / プロテアーゼ / カルシウムシグナル / 遺伝子改変マウス / 神経変性疾患 / アルツハイマー病 / 学習記憶

Research Abstract

In this study, we have analyzed the motor abnoromality in calpain-1 and calpain-2 double knockout mice. Neuron-specific deleted knockout showed abnormalities in motor and/or visual capacity in Morris water maze test. Then, we identified several substrates of calpain-1 and calpain-2, which relate the functional abnormalities, by masspectrometic technique and the iTRAQ method. However, some of the substrates were not cleaved so much by calpain. Thus, we are trying to identify calpain substrates in cell culture system using calcium ionophores.

Research Products

• [Journal Article] Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3). (2013)
  • Author(s): Hubener J, Weber JJ, Richter C, Honold L, Weiss A, Murad F, Breuer P, Wullner U, Bellstedt P, Paquet-Durand F, Takano J, Saido TC, Riess O, Nguyen HP.
  • Journal Title: Hum Mol Genet. Volume: 22(3) Pages: 508-18
  • Peer Reviewed
• [Journal Article] Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3). (2013)
  • Author(s): Hübener J
  • Journal Title: Hum Mol Genet Volume: 22 Issue: 3 Pages: 508-18
  • DOI: 10.1093/hmg/dds449
  • Peer Reviewed
• [Journal Article] A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology. (2012)
  • Author(s): Yamashita T, Hideyama T, Hachiga K, Teramoto S, Takano J, Iwata N, Saido TC, Kwak S.
  • Journal Title: Nat Commun. Volume: 3 Pages: 130-130
  • Peer Reviewed
• [Journal Article] Metabolic stress response implicated in diabetic retinopathy: the role of calpain, and the therapeutic impact of calpain inhibitor. (2012)
  • Author(s): Shanab AY, Nakazawa T, Ryu M, Tanaka Y, Himori N, Taguchi K, Yasuda M, Watanabe R, Takano J, Saido T, Minegishi N, Miyata T, Abe T, Yamamoto M.
  • Journal Title: Neurobiol Dis. Volume: 48(3) Pages: 556-67
  • Peer Reviewed
• [Journal Article] Calpastatin overexpression limits calpain-mediated proteolysis and behavioral deficits following traumatic brain injury. (2012)
  • Author(s): Schoch KM, Evans HN, Brelsfoard JM, Madathil SK, Takano J, Saido TC, Saatman KE.
  • Journal Title: Exp Neurol. Volume: 236(2) Pages: 371-82
  • Peer Reviewed
• [Journal Article] Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology. (2012)
  • Author(s): Higuchi M, Iwata N, Matsuba Y, Takano J, Suemoto T, Maeda J, Ji B, Ono M, Staufenbiel M, Suhara T, Saido TC.
  • Journal Title: FASEB J. Volume: 26(3) Pages: 1204-17
  • Peer Reviewed
• [Journal Article] Critical role of calpain in axonal damage-induced retinal ganglion cell death. (2012)
  • Author(s): Ryu M, Yasuda M, Shi D, Shanab AY, Watanabe R, Himori N, Omodaka K, Yokoyama Y, Takano J, Saido T, Nakazawa T.
  • Journal Title: J Neurosci Res. Volume: 90(4) Pages: 802-15
  • Peer Reviewed
• [Journal Article] A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology (2012)
  • Author(s): Yamashita T, Hideyama T, Hachiga K, Teramoto S, Takano J, Iwata N, Saido TC, and Kwak S
  • Journal Title: Nat Commun Volume: 3 Issue: 1 Pages: 1307-1307
  • DOI: 10.1038/ncomms2303
  • Peer Reviewed
• [Journal Article] Critical role of calpain in axonal damage-induced retinal ganglion cell death (2012)
  • Author(s): Molin Ryu, Toru Nakazawa, et al
  • Journal Title: J Neuroci Res Volume: 90 Issue: 4 Pages: 802-815
  • DOI: 10.1002/jnr.22800
  • Peer Reviewed
• [Journal Article] Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology (2012)
  • Author(s): Makoto Higuchi, Nobuhisa Iwata, Yukio Matsuba, Jiro Takano, Takahiro Suemoto, Jun Maeda, Bin Ji, Maiko Ono, Matthias Staufenbiel, Tetsuya Suhara, Takaomi C.Saido
  • Journal Title: The FASEB Journal Volume: (In press)
  • Peer Reviewed
• [Journal Article] Vital role of the calpain-calpastatin system for placental-integrity-dependent embryonic survival. (2011)
  • Author(s): Takano J, Mihira N, Fujioka R, Hosoki E, Chishti AH, Saido TC.
  • Journal Title: Mol Cell Biol. Volume: 31(19) Pages: 4097-106
  • Peer Reviewed
• [Journal Article] Potent amyloidogenicity and pathogenicity of Aβ43. (2011)
  • Author(s): Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, Matsuba Y, Yamada K, Nilsson P, Takano J, Nishimura M, Iwata N, Van Broeckhoven C, Ihara Y, Saido TC.
  • Journal Title: Nat Neurosci. Volume: 14(8) Pages: 1023-32
  • NAID: 120006985066
  • Peer Reviewed
• [Journal Article] Cleavage of the vesicular GABA transporter under excitotoxic conditions is followed by accumulation of the truncated transporter in nonsynaptic sites. (2011)
  • Author(s): Gomes JR, Lobo AC, Melo CV, Inacio AR, Takano J, Iwata N, Saido TC, de Almeida LP, Wieloch T, Duarte CB.
  • Journal Title: J Neurosci. Volume: 31(12) Pages: 4622-35
  • Peer Reviewed
• [Journal Article] Calpastatin, an endogenous calpain-inhibitor protein, regulates the cleavage of the Cdk5 activator p35 to p25. (2011)
  • Author(s): Sato K, Minegishi S, Takano J, Plattner F, Saito T, Asada A, Kawahara H, Iwata N, Saido TC, Hisanaga S.
  • Journal Title: J Neurochem. Volume: 117(3) Pages: 504-15
  • Peer Reviewed
• [Journal Article] Nicotinic acetylcholine receptor α1 promotes calpain-1 activation and macrophage inflammation in hypercholesterolemic nephropathy. (2011)
  • Author(s): Zhang G, Thomas AL, Marshall AL, Kernan KA, Su Y, Zheng Y, Takano J, Saido TC, Eddy AA.
  • Journal Title: Lab Invest. Volume: 91(1) Pages: 106-23
  • Peer Reviewed
• [Journal Article] Calpastatin, an endogenous calpain-inhibitor protein, regulates the cleavage of the Cdk5 activator p35 to p25 (2011)
  • Author(s): Sato, et al
  • Journal Title: J.Neurochem. Volume: 117 Issue: 3 Pages: 504-515
  • DOI: 10.1111/j.1471-4159.2011.07222.x
  • Peer Reviewed
• [Journal Article] Cleavage of the vesicular GABA transporter under excitotoxic conditions is followed by accumulation of the truncated transporter in nonsynaptic sites (2011)
  • Author(s): Joao R.Gomes, Andrea C.Lobo, Carlos V.Melo, Ana R.Inacio, Jiro Takano, Nobuhisa Iwata, Takaomi C.Saido, Luis P.de Almeida, Tadeusz Wieloch, Carlos B.Duarte
  • Journal Title: The Journal of Neuroscience Volume: 31 Issue: 12 Pages: 4622-4635
  • DOI: 10.1523/jneurosci.3541-10.2011
  • Peer Reviewed
• [Journal Article] Potent amyloidogenicity and pathogenicity of Aβ43 (2011)
  • Author(s): Takashi Saito, Takahiro Suemoto, Nathalie Brouwers, Kristel Sleegers, Satoru Funamoto, Naomi Mihira, Yukio Matsuba, Kazuyuki Yamada, Per Nilsson, Jiro Takano, Masaki Nishimura, Nobuhisa Iwata, Christine Van Broeckhoven, Yasuo Ihara, Takaomi C Saido
  • Journal Title: Nature Neuroscience Volume: 14 Issue: 8 Pages: 1023-1032
  • DOI: 10.1038/nn.2858
  • NAID: 120006985066
  • Peer Reviewed
• [Journal Article] Vital role of the calpain-calpastatin system for placental-integrity-depen dent embryonic survival (2011)
  • Author(s): Jiro Takano, Naomi Mihira, Ryo Fujioka, Emi Hosoki, Athar H.Chishti, Takaomi C.Saido
  • Journal Title: Molecular and Cellular Biology Volume: 31 Issue: 19 Pages: 4097-4106
  • DOI: 10.1128/mcb.05189-11
  • Peer Reviewed
• [Presentation] 胎盤発生における細胞内プロテアーゼ・カルパインの生理機能 (2012)
  • Author(s): 高野二郎
  • Organizer: 名古屋市立大学産科婦人科学生殖・遺伝セミナー
  • Place of Presentation: 愛知
  • Year and Date: 2012-07-07
• [Presentation] 成体における細胞内プロテアーゼ・カルパインの機能 (2012)
  • Author(s): 高野二郎
  • Organizer: 第2回東北眼科疾患病態研究会
  • Place of Presentation: 宮城
  • Year and Date: 2012-02-28
• [Presentation] 脳内カルパイン様プロテアーゼの解析 (2011)
  • Author(s): 高野二郎
  • Organizer: 日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-23
• [Presentation] Analysis of calpain-like protease in brain (2011)
  • Author(s): Jiro Takano, Takaomi C.Saido
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都
  • Year and Date: 2011-09-23
• [Presentation] 遺伝子改変マウスから分かったカルパイン-1 とカルパイン-2 の機能 (2011)
  • Author(s): 高野二郎
  • Organizer: Conference for Biosignal and Medcine
  • Place of Presentation: 三重
  • Year and Date: 2011-09-01
• [Presentation] Genetic analysis of the calpain-calpastatin system using calpain-1, calpain-2, and calpastatin knockout mice (2010)
  • Author(s): Jiro Taknao
  • Organizer: FASEB Summer Research Conference
  • Place of Presentation: Carefree, Arizona
  • Year and Date: 2010-07-28
• [Patent(Industrial Property Rights)] アルツハイマー病モデル動物およびその用途 (2010)
  • Inventor(s): 西道隆臣、岩田修永、斎藤貴志、末元隆寛、高野二郎
  • Industrial Property Rights Holder: 独立行政法人理化学研究所
  • Industrial Property Number: 2006-170776
  • Acquisition Date: 2010-06-29