Pathogenesis-based therapy development for polyglutamine diseases

2008 Fiscal Year Final Research Report

• Project/Area Number: 19209033
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: SOBUE Gen Nagoya University, 大学院・医学系研究科, 教授 (20148315)
• Co-Investigator(Kenkyū-buntansha): TANAKA Fumiaki 名古屋大学, 大学院・医学系研究科, 准教授 (30378012) ; 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, 高等研究院 (50402566)
• Co-Investigator(Renkei-kenkyūsha): DOYU Manabu 愛知医科大学, 医学部, 教授 (90293703)
• Project Period (FY): 2007 – 2008
• Keywords: 神経分子病態学 / ポリグルタミン / 分子シャペロン / ユビキチンープロテアソーム / 球脊髄性筋萎縮症

Research Abstract

遺伝性運動ニューロン疾患である球脊髄性筋萎縮症(SBMA)のマウスモデルにおいて、分子シャペロンやユビキチン-プロテアソーム系の機能を増強することにより神経変性の進行が抑えられることを明らかにした。また、すでにSBMAのマウスモデルにおいて病態抑止効果が明らかとなっているアンドロゲン低下療法について、患者を対象とした第II相臨床試験を実施し、本治療法が患者においても病態を抑えることを明らかにした。

Research Products

• [Journal Article] Pathogenesis-targeting Therapeutics for Spinal and Bulbar Muscular Atrophy (SBMA) (2009)
  • Author(s): Suzuki K, Katsuno M, Banno H, Sobue G
  • Journal Title: Neuropathology (in press)
  • Peer Reviewed
• [Journal Article] Neuropathology and therapeutic intervention in spinal and bulbar muscular atrophy (2009)
  • Author(s): Banno H, Katsuno M, Suzuki K, Tanaka F, Sobue G
  • Journal Title: Int. J. Mol. Sci (in press)
  • 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, 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)
  • Peer Reviewed
• [Journal Article] Getting a handle on Huntington's disease : the case for cholesterol (2009)
  • Author(s): Katsuno M, Adachi H, Sobue G
  • Journal Title: Nat. Med 15 Pages: 253-254
  • Peer Reviewed
• [Journal Article] Sopher BL, Lin A, Fischbeck KH, Ellerby LM, Morrison RS, Taylor JP, La Spada AR. 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
  • 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, 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
  • Peer Reviewed
• [Journal Article] 17-DMAG ameliorates polyglutamine-mediated motor neuron degeneration through well-preserved proteasome function in a 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
  • Peer Reviewed
• [Journal Article] Walking capacity evaluated by the 6-minute walk test in spinal and bulbar muscular atrophy (2008)
  • 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: 946-971
  • Peer Reviewed
• [Journal Article] Molecular Genetics and Biomarkers of Polyglutamine Diseases (2008)
  • Author(s): Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Adachi H, Tanaka F, Sobue G
  • Journal Title: Current Mol. Med. 8 Pages: 221-234
  • Peer Reviewed
• [Journal Article] Cognitive impairment in spinocerebellar ataxia type 6 (2008)
  • Author(s): Suenaga M, Kawai Y, Watanabe H, Atsuta N, Ito M, Tanaka F, Katsuno M, Fukatsu H, Naganawa S, Sobue G
  • Journal Title: J. Neurol .Neurosurg. Psychiatry 79 Pages: 496-499
  • Peer Reviewed
• [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
  • Peer Reviewed
• [Journal Article] Therapeutic strategies for spinal and bulbar muscular atrophy (SBMA) (2007)
  • Author(s): Katsuno M, Banno H, Suzuki K, Takeuchi Y, Minamiyama M, Waza M, Adachi H, Tanaka F, Sobue G
  • Journal Title: Drug Future 32 Pages: 907-917
  • Peer Reviewed
• [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
  • Peer Reviewed
• [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
  • Peer Reviewed
• [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: Nat. Med 13 Pages: 348-353
  • Peer Reviewed
• [Presentation] An oral Hsp90 inhibitor ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model (2008)
  • Author(s): Adachi H, Tokui K, Waza M, Katsuno M, Minamiyama M, Doi H, Tanaka F, Sobue G
  • Organizer: Neuroscience 2009
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20081115-19
• [Presentation] Skeletal muscle involvement in spinal and bulbar muscular atrophy (2008)
  • Author(s): Katsuno M, Kawashima M, Banno H, Suzuki K, Takeuchi Y, Suga N, Adachi H, Tanaka F, Sobue G
  • Organizer: The 19th International Symposium on ALS/MND
  • Place of Presentation: Birmingham, UK
  • Year and Date: 20081103-05
• [Presentation] 神経変性疾患の病態に基づく治療開発 (2008)
  • Author(s): 祖父江元
  • Organizer: 第四回神経内科の基礎と臨床
  • Place of Presentation: 京都
  • Year and Date: 2008-11-21
• [Presentation] 分子シャペロンによる神経変性疾患の治療への展望 (2008)
  • Author(s): 祖父江元
  • Organizer: 日本ハイパーサーミア学会第25回大会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-09-12
• [Presentation] 神経変性疾患の病態抑止治療 (2008)
  • Author(s): 祖父江元
  • Organizer: 第39回日本内科学会北海道支部生涯教育講演会
  • Place of Presentation: 北海道
  • Year and Date: 2008-06-16
• [Presentation] 神経変性疾患の分子標的治療 : 球脊髄性筋萎縮症を中心に (2008)
  • Author(s): 祖父江元
  • Organizer: 第49回日本神経病理学会総会学術集会シンポジウムI「末梢神経・筋疾患の臨床病理-病因解明と治療開発にはたす新たな役割-」
  • Place of Presentation: 東京
  • Year and Date: 2008-05-20
• [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、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: 2008-05-16
• [Presentation] 神経変性疾患の分子標的治療への展望-SBMAを中心に- (2008)
  • Author(s): 祖父江元
  • Organizer: Academic Conference in Tokyo
  • Place of Presentation: 東京
  • Year and Date: 2008-02-07
• [Presentation] Myocardial involvement in spinal and bulbar muscular atrophy (2007)
  • Author(s): Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Tanaka F, Sobue G
  • Organizer: 18th International symposium on ALS/MND
  • Place of Presentation: Toronto, Canada
  • Year and Date: 20071201-03
• [Presentation] CHIP overexpression reduces the mutant AR protein and ameliorates phenotypes of the SBMA transgenic mouse model (2007)
  • Author(s): Adachi H, Waza M, Tokui K, Katsuno M, Tanaka F, Sobue G
  • Organizer: Neuroscience 2007
  • Place of Presentation: San Diego, USA
  • Year and Date: 20071103-07
• [Presentation] Translational approaches for polyglutamine disease (2007)
  • Author(s): Sobue G
  • Organizer: 第4回21世紀COE国際シンポジウム(The 21st century center for excellence (COE) program 4th international symposium on functional molecules linked to neurodegeneration and oncogenesis-toward molecular targeted therapy-)
  • Place of Presentation: Nagoya, Japan
  • Year and Date: 20071025-26
• [Presentation] Mutant SOD1 and protein aggregation/degradation in motoneuronal cells (2007)
  • Author(s): Sobue G
  • Organizer: Mutant SOD1 and familial ALS : from molecule to man
  • Place of Presentation: Milano, Italy
  • Year and Date: 20070913-06
• [Presentation] Reversible dysfunction in polyglutamine disease (2007)
  • Author(s): Sobue G
  • Organizer: Neuro2007
  • Place of Presentation: Yokohama, Japan
  • Year and Date: 20070910-12
• [Presentation] 分子シャペロンによる神経変性疾患の治療への展望 (2007)
  • Author(s): 祖父江元
  • Organizer: 第2回臨床ストレス応答学会大会ランチョンセミナー
  • Place of Presentation: 福岡
  • Year and Date: 2007-11-30
• [Presentation] 神経変性疾患の病態抑止治療 (2007)
  • Author(s): 祖父江元
  • Organizer: 第48回日本神経学会総会 シンポジウム「神経変性疾患の動物モデル」
  • Place of Presentation: 名古屋
  • Year and Date: 2007-05-16