Development of animal model for sporadic ALS

• Project/Area Number: 19390238
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: TANAKA Fumiaki Nagoya University, 大学院・医学系研究科, 准教授 (30378012)
• Co-Investigator(Kenkyū-buntansha): SOBUE Gen 名古屋大学, 大学院・医学系研究科, 教授 (20148315) ; ADACHI Hiroaki 名古屋大学, 大学院・医学系研究科, COE特任講師 (40432257) ; KATSUNO Masahisa 名古屋大学, 高等研究院, 特任講師 (50402566) ; IIJIMA Masahiro 名古屋大学, 大学院・医学系研究科, COE特任助教 (40437041) ; 道勇 学 愛知医科大学, 医学部, 特任教授 (90293703)
• Co-Investigator(Renkei-kenkyūsha): DOYU Manabu 愛知医科大学, 医学部, 教授 (90293703)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2008: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000); Fiscal Year 2007: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000)
• Keywords: ALS / 運動ニューロン / dynactin1 / cyclin C / 線虫 / 疾患モデル / dynactinl / 遺伝子発現解析

Research Abstract

孤発性ALS患者脊髄運動ニューロンにおいて、神経変性過程の初期より発現が低下しているdynactin1の発現変化を再現する線虫モデルを作成した。このモデルでは、進行性の運動機能障害、運動ニューロン変性を認め、患者運動ニューロンで観察されたcyclin Cの発現増加、核への局在変化を再現していた。これらのことより、dynactin1ノックダウン線虫は孤発性ALSの病態、特に細胞周期関連因子の異常を反映する重要な疾患モデルであると考えられた。

Research Products

• [Journal Article] The case for cholesterol (2009)
  • Author(s): Katsuno M, Adachi H, Sobue G.
  • Journal Title: .Nature Med. (in press)
• [Journal Article] Correlation between pyramidal tract degeneration and widespread white matter involvement in amyotrophic lateral sclerosis: A study with tractography and diffusion-tensor imaging (2009)
  • Author(s): Senda J, Ito M, Watanabe H, Atsuta N, Kawai Y, Katsuno M, Tanaka F, Naganawa S, Fukatsu H, Sobue G.
  • Journal Title: Amyotroph Lateral Scler. (in press)
• [Journal Article] Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk (2009)
  • Author(s): Young JE, Garden GA, Martinez RA, Tanaka F, Sandoval CM, Smith AC, Sopher BL, Lin A, Fischbeck KH, Ellerby LM, Morrison RS, Taylor JP, La Spada AR.
  • Journal Title: J Neurosci. 29 Pages: 1987-1997
• [Journal Article] Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy (2009)
  • Author(s): Banno H, Katsuno M, Suzuki K, Takeuchi Y, Kawashima M, Suga N, Takamori M, Ito M, Nakamura T, Matsuo K, Yamada S, Oki Y, Adachi H, Minamiyama M, Waza M, Atsuta N, Watanabe H, Fujimoto Y, Nakashima T, Tanaka F, Doyu M, Sobue G.
  • Journal Title: Ann Neurol. 65 Pages: 140-150
• [Journal Article] 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse (2009)
  • Author(s): Tokui K, Adachi H, Waza M, Katsuno M, Minamiyama M, Doi H, Tanaka K, Hamazaki J, Murata S, Tanaka F, Sobue G.
  • Journal Title: Hum Mol Genet 18 Pages: 898-910
• [Journal Article] Research Committee on the Neurodegenerative Diseases of Japan. Age at onset influences on wide-ranged clinical features of sporadic amyotrophic lateral sclerosis (2009)
  • Author(s): Atsuta N, Watanabe H, Ito M, Tanaka F, Tamakoshi A, Nakano I, Aoki M, Tsuji S, Yuasa T, Takano H, Hayashi H, Kuzuhara S, Sobue G.
  • Journal Title: J Neurol Sci. 276 Pages: 163-169
• [Journal Article] Walking capacity evaluated by the 6-minute walk test in spinal and bulbar muscular atrophy (2009)
  • Author(s): Takeuchi Y, Katsuno M, Banno H, Suzuki K, Kawashima M, Atsuta N, Ito M, Watanabe H, Tanaka F, Sobue G
  • Journal Title: Muscle Nerve 38 Pages: 964-971
• [Journal Article] The case for cholesterol (2009)
  • Author(s): Katsuno M, et al.
  • Journal Title: Nature Med (印刷中)
  • Peer Reviewed
• [Journal Article] Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk (2009)
  • Author(s): Young JE, et al.
  • Journal Title: J Neurosci 29 Pages: 1987-1997
  • Peer Reviewed
• [Journal Article] Phase 2 trial of leuprorelin in patients with spinal and bulbar muscular atrophy. (2009)
  • Author(s): Banno H, et al.
  • Journal Title: Ann Neurol 65 Pages: 140-150
  • Peer Reviewed
• [Journal Article] Correlation between pyramidal tract degeneration and widespread white matter involvement in amyotrophic lateral sclerosis : A study with tractography and diffusion-tensor imaging (2009)
  • Author(s): Senda J, et al.
  • Journal Title: Amyotroph Lateral Scler (印刷中)
  • Peer Reviewed
• [Journal Article] 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in an SBMA model mouse (2009)
  • Author(s): Tokui K, et al.
  • Journal Title: Hum Mol Genet 18 Pages: 898-910
  • Peer Reviewed
• [Journal Article] Age at onset influences on wide-ranged clinical features of sporadic amyotrophic lateral sclerosis (2009)
  • Author(s): Atsuta N, et al.
  • Journal Title: J Neurol Sci 276 Pages: 163-169
  • Peer Reviewed
• [Journal Article] A strategy for developing effective amyotropic lateral sclerosis pharmacotherapy: from clinical trials to novel pharmacotherapeutic strategies (2008)
  • Author(s): Yamamoto M, Tanaka F, Tatsumi H, Sobue G.
  • Journal Title: Expert Opin Pharmacother 9 Pages: 1845-1857
• [Journal Article] Molecular genetics and biomarkers of polyglutamine diseases (2008)
  • Author(s): Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Tanaka F, Adachi H, Sobue G.
  • Journal Title: Curr Mol Med. 8 Pages: 221-234
• [Journal Article] CAG repeat size correlates to electrophysiological motor and sensory phenotypes in SBMA (2008)
  • Author(s): Suzuki K, Katsuno M, Banno H, Takeuchi Y, Atsuta N, Ito M, Watanabe H, Yamashita F, Hori N, Nakamura T, Hirayama M, Tanaka F, Sobue G.
  • Journal Title: Brain 131 Pages: 229-239
• [Journal Article] Refractory Peripheral Neuropathy Study Group of Japan. Prevalence and incidence rates of chronic inflammatory demyelinating polyneuropathy in the Japanese population (2008)
  • Author(s): Iijima M, Koike H, Hattori N, Tamakoshi A, Katsuno M, Tanaka F, Yamamoto M, Arimura K, Sobue G.
  • Journal Title: J Neurol Neurosurg Psychiatry 79 Pages: 1040-1043
• [Journal Article] Walking capacity evaluated by the 6-minute walk test in spinal and bulbar muscular atrophy (2008)
  • Author(s): Takeuchi Y, et al.
  • Journal Title: Muscle Nerve 38 Pages: 964-971
  • Peer Reviewed
• [Journal Article] A strategy for developing effective amyotropic lateral sclerosis pharmacotherapy : from clinical trials to novel pharmacotherapeutic strategies (2008)
  • Author(s): Yamamoto M, et al.
  • Journal Title: Expert Opin Pharmacother 9 Pages: 1845-1857
  • Peer Reviewed
• [Journal Article] Molecular genetics and biomarkers of polyglutamine diseases (2008)
  • Author(s): Katsuno M, et al.
  • Journal Title: Curr Mol Med 8 Pages: 221-234
  • Peer Reviewed
• [Journal Article] CAG repeat size correlates to electrophysiological motor and sensory phenotypes in SBMA (2008)
  • Author(s): Suzuki K, et al.
  • Journal Title: Brain 131 Pages: 229-239
  • Peer Reviewed
• [Journal Article] CAG repeat size correlates to electrophysiological motor and sensory phenotypes in SBMA. (2008)
  • Author(s): Suzuki K, et. al.
  • Journal Title: Brain 131 Pages: 229-239
  • Peer Reviewed
• [Journal Article] Gene expressions specifically detected in motor neurons (dynactin 1, early growth response 3, acetyl-CoA transporter, death receptor 5, and cyclin C) differentially correlate to pathologic markers in sporadic amyotrophic lateral sclerosis (2007)
  • Author(s): Jiang YM, Yamamoto M, Tanaka F, Ishigaki S, Katsuno M, Adachi H, Niwa J, Doyu M, Yoshida M, Hashizume Y, Sobue G.
  • Journal Title: J Neuropathol Exp Neurol 66 Pages: 617-627
• [Journal Article] CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model (2007)
  • Author(s): Adachi H, Waza M, Tokui K, Katsuno M, Minamiyama M, Tanaka F, Doyu M, Sobue G.
  • Journal Title: J Neurosci 27 Pages: 5115-5126
• [Journal Article] Disulfide bond mediates aggregation, toxicity, and ubiquitylation of familial amyotrophic lateral sclerosis-linked mutant SOD1 (2007)
  • Author(s): Niwa J, Yamada S, Ishigaki S, Sone J, Takahashi M, Katsuno M, Tanaka F, Doyu M, Sobue G.
  • Journal Title: J Biol Chem 282 Pages: 28087-28095
• [Journal Article] ASC-J9 ameliorates spinal and bulbar muscular atrophy phenotype via degradation of androgen receptor (2007)
  • Author(s): Yang Z, Chang YJ, Yu IC, Yeh S, Wu CC, Miyamoto H, Merry DE, Sobue G, Chen LM, Chang SS, Chang C.
  • Journal Title: Nauret Med 13 Pages: 348-353
• [Journal Article] Scientific highlights. 17th International Symposium on ALS/MND Yokohama, Japan, November 30, 2006 through December 2, 2006 (2007)
  • Author(s): Sobue G.
  • Journal Title: Amyotroph Lateral Scler 8 Pages: 121-123
• [Journal Article] Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy (2007)
  • Author(s): Adachi H, Waza M, Katsuno M, Tanaka F, Doyu M, Sobue G.
  • Journal Title: Neuropathol Appl Neurobiol 33 Pages: 135-151
• [Journal Article] Dorfin-CHIP chimeric proteins potently ubiquitylate and degrade familial ALS-related mutant SOD1 proteins and reduce their cellular toxicity (2007)
  • Author(s): Ishigaki S, Niwa J, Yamada S, Takahashi M, Ito T, Sone J, Doyu M, Urano F, Sobue G.
  • Journal Title: Neurobiol Dis 25 Pages: 331-341
• [Journal Article] Gene expressions specifically detected in motor neurons (dynactin 1, early growth response 3, acetyl-CoA transporter, death receptor 5, and cyclin C) differentially correlate to pathologic markers in sporadic amyotrophic lateral sclerosis (2007)
  • Author(s): Jiang YM, et. al.
  • Journal Title: J Neuropathol Exp Neurol 66 Pages: 617-627
  • Peer Reviewed
• [Journal Article] Disulfide bond mediates aggregation, toxicity, and ubiquitylation of familial amyotrophic lateral sclerosis-linked mutant SOD1 (2007)
  • Author(s): Niwa J, et. al.
  • Journal Title: J Biol Chem 282 Pages: 28087-28095
  • Peer Reviewed
• [Journal Article] CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrphy transgenic mouse model (2007)
  • Author(s): Adachi H, et. al.
  • Journal Title: J Neurosci 27 Pages: 5115-5126
  • Peer Reviewed
• [Journal Article] Dorfin-CHIP chimeric proteins potently ubiquitylate and degrade familial ALS-related mutant SOD1 proteins and reduce their cellular toxicity (2007)
  • Author(s): Ishigaki S, et. al.
  • Journal Title: Neurobiol Dis 25 Pages: 331-341
  • Peer Reviewed
• [Presentation] 孤発性ALS病態関連分子の探索と疾患モデルの開発 (2008)
  • Author(s): 田中章景、和座雅浩、丹羽淳一、祖父江 元
  • Organizer: 第49回日本神経学会総会シンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-17
• [Presentation] 孤発性ALS病ALS病態関連分子の探索と疾患モデルの開発 (2008)
  • Author(s): 田中章景, ら
  • Organizer: 第49回日本神経学会総会シンポジウム
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-17
• [Presentation] Dynactin-1ノックダウン線虫モデルの作成 (2008)
  • Author(s): 和座雅浩、田中章景、蒋月梅、黄哲、勝野雅央、足立弘明、山本正彦、祖父江元
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-16
• [Presentation] 孤発性ALS疾患モデルの開発 : dynactin1ノックダウン細胞の解析 (2007)
  • Author(s): 田中章景、黄哲、蒋月梅、松尾幸治、和座雅浩、山本正彦、道勇学、祖父江元
  • Organizer: 第48回日本神経学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-05-16