Elucidation of cellular signaling defect and mechanism of cell-specific degeneration in polyglutamine diseases

• Project/Area Number: 21689024
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: KATSUNO Masahisa Nagoya University, 大学院・医学系研究科, 特任准教授 (50402566)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥27,820,000 (Direct Cost: ¥21,400,000、Indirect Cost: ¥6,420,000); Fiscal Year 2010: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000); Fiscal Year 2009: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000)
• Keywords: ポリグルタミン病 / 運動ニューロン / TGF-βシグナル / 球脊髄性筋萎縮症 / ポリグルタミン / アンドロゲン受容体 / HSF-1 / HSP70 / 分子シャペロン / 神経変性 / NF-Y / TGF-beta / 転写障害 / Smad2

Research Abstract

Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins induce transcriptional dysregulation, the down-stream molecular events have remained elusive. Here we examined whether TGF-βsignaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3 is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human AR. The pathogenic AR inhibits the transcription of TGF-βreceptor type II (TβRII), via abnormal interactions with NF-Y and p300/CBP-associated factor (P/CAF). Furthermore, overexpression of TβRII dampens the cytotoxicity of the pathogenic AR. The present study thus indicates that disruption of TGF-βdue to the transcriptional dysregulation of TβRII is associated with polyglutamine-induced motor neuron damage in SBMA.

Research Products

• [Journal Article] Dutasteride for spinal and bulbar muscular atrophy : another advance towards disease-modifying therapy. (2011)
  • Author(s): Banno H, Katsuno M, Suzuki K, Sobue .
  • Journal Title: Lancet Neurol. 10 Pages: 113-115
• [Journal Article] Transforming growth factor-β signaling in motor neuron diseases. (2011)
  • Author(s): Katsuno M, Adachi H, Banno H, Suzuki K, Tanaka F, Sobue G.
  • Journal Title: Current Mol Med. 11 Pages: 48-56
• [Journal Article] icroarray analysis of gene expression by skeletal muscle of three mouse models of kennedy disease/spinal bulbar muscular atrophy. (2010)
  • Author(s): Mo K, Razak Z, Rao P, Yu Z, Adachi H, Katsuno M, Sobue G, Lieberman AP, Westwood JT, Monks DA.M
  • Journal Title: PLoS One 5
• [Journal Article] for the Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) study group.Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study) : a multicentre, randomised, double-blind, placebo-controlled trial. (2010)
  • Author(s): Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Yabe I, Sasaki H, Aoki M, Morita M, Nakano I, Kanai K, Ito S, Ishikawa K, Mizusawa H, Yamamoto T, Tsuji S, Hasegawa K, Shimohata T, Nishizawa M, Miyajima H, Kanda F, Watanabe Y, Nakashima K, Tsujino A, Yamashita T, Uchino M, Fujimoto Y, Tanaka F, Sobue G
  • Journal Title: Lancet Neurol. 9 Pages: 875-884
• [Journal Article] Disrupted TGF-beta signaling in spinal and bulbar muscular atrophy. (2010)
  • Author(s): Katsuno M, Adachi H, Minamiyama M, Waza M, Doi H, Kondo N, Mizoguchi H, Nitta A, Yamada K, Banno H, Suzuki K, Tanaka F, Sobue G.
  • Journal Title: J Neurosci. 30 Pages: 5702-5712
• [Journal Article] The profile of motor unit number estimation (MUNE) in spinal and bulbar muscular atrophy. (2010)
  • Author(s): Suzuki K, Katsuno M, Banno H, Takeuchi Y, Kawashima M, Suga N, Hashizume A, Hama T, Uchida K, Yamashita F, Nakamura T, Hirayama M, Tanaka F, Sobue G.
  • Journal Title: J Neurol Neurosurg Psychiatry 81 Pages: 567-571
• [Journal Article] Microarray analysis of gene expression by skeletal muscle of three mouse models of kennedy disease/spinal bulbar muscular atrophy. (2010)
  • Author(s): Mo K, Razak Z, Rao P, Yu Z, Adachi H, Katsuno M, Sobue G, Lieberman AP, Westwood JT, Monks DA.
  • Journal Title: PLoS One Volume: 5
  • Peer Reviewed
• [Journal Article] Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study) : a multicentre, randomised, double-blind, placebo-controlled trial. (2010)
  • Author(s): Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Yabe I, Sasaki H, Aoki M, Morita M, Nakano I, Kanai K, Ito S, Ishikawa K, Mizusawa H, Yamamoto T, Tsuji S, Hasegawa K, Shimohata T, Nishizawa M, Miyajima H, Kanda F, Watanabe Y, Nakashima K, Tsujino A, Yamashita T, Uchino M, Fujimoto Y, Tanaka F, Sobue G ; for the Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) study gtoup.
  • Journal Title: Lancet Neurol. Volume: 9 Pages: 875-884
  • Peer Reviewed
• [Journal Article] Disrupted TGF-beta signaling in spinal and bulbar muscular atrophy. (2010)
  • Author(s): Katsuno M, Adachi H, Minamiyama M, Waza M, Doi H, Kondo N, Mizoguchi H, Nitta A, Yamada K, Banno H, Suzuki K, Tanaka F, Sobue G.
  • Journal Title: J Neurosci. Volume: 30 Pages: 5702-5707
  • Peer Reviewed
• [Journal Article] The profile of motor unit number estimation (MUNE) in spinal and bulbar muscular atrophy. (2010)
  • Author(s): Suzuki K, Katsuno M, Banno H, Takeuchi Y, Kawashima M, Suga N, Hashizume A, Hama T, Uchida K, Yamashita F, Nakamura T, Hirayama M, Tanaka F, Sobue G.
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 81 Pages: 567-571
  • Peer Reviewed
• [Journal Article] Dutasteride for spinal and bulbar muscular atrophy : another advance to wards disease-modifying therapy. (2010)
  • Author(s): Banno H, Katsuno M, Suzuki K, Sobue G.
  • Journal Title: Lancet Neurol. Volume: 10 Pages: 113-115
• [Journal Article] Transforming growth factor-beta signaling in motor neuron diseases. (2010)
  • Author(s): Katsuno M, Adachi H, Banno H, Suzuki K, Tanaka F, Sobue G.
  • Journal Title: Current Mol Med. Volume: 11 Pages: 48-56
  • Peer Reviewed
• [Journal Article] Clinical features and molecular mechanisms of spinal and bulbar muscular atrophy (SBMA). (2010)
  • Author(s): Katsuno M, Banno H, Suzuki K, Adachi H, Tanaka F, Sobue G.
  • Journal Title: Adv Exp Med Biol. Volume: 685 Pages: 64-74
  • Peer Reviewed
• [Journal Article] Dorfin ameliorates phenotypes in a transgenic mouse model of amyotrophic lateral sclerosis. (2010)
  • Author(s): Sone, J., Niwa, J.I., Kawai, K., Ishigaki, S., Yamada, S.I., Adachi, H., Katsuno, M., Tanaka, F., Doyu, M., Sobue, G.
  • Journal Title: J Neurosci Res. Volume: 88 Pages: 123-135
  • Peer Reviewed
• [Journal Article] Heat shock proteins in neurodegenerative diseases : Pathogenic roles and therapeutic implications. (2009)
  • Author(s): Adachi H, Katsuno M, Waza M, Minamiyama M, Tanaka F, Sobue G.
  • Journal Title: Int J Hyperthermia 25 Pages: 647-654
• [Journal Article] Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. (2009)
  • Author(s): Palazzolo I, Stack C, Kong L, Musaro A, Adachi H, Katsuno M, Sobue G, Taylor JP, Sumner CJ, Fischbeck KH, Pennuto M.
  • Journal Title: Neuron 63 Pages: 316-328
• [Journal Article] TDP-43 Depletion Induces Neuronal Cell Damage through Dysregulation of Rho Family GTPases. (2009)
  • Author(s): Iguchi Y, Katsuno M, Niwa J, Yamada S, Sone J, Waza M, Adachi H, Tanaka F, Nagata K, Arimura N, Watanabe T, Kaibuchi K, Sobue G.
  • Journal Title: J Biol Chem. 284 Pages: 22059-22066
• [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
• [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] 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. 10 Pages: 1000-1012
• [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
• [Journal Article] Single nucleotide polymorphism of TAG-1 influences IVIg responsiveness of Japanese patients with CIDP. (2009)
  • Author(s): Iijima, M., Tomita, M., Morozumi, S., Kawagashira, Y., Nakamura, T., Koike, H., Katsuno, M., Hattori, N., Tanaka, F., Yamamoto, M., Sobue, G.
  • Journal Title: Neurology Volume: 73 Pages: 1348-1352
  • Peer Reviewed
• [Journal Article] Overexpression of IGF-1 in muscle attenuates disease in a mouse model of spinal and bulbar muscular atrophy. (2009)
  • Author(s): Palazzolo, I., Stack, C., Kong, L., Musaro, A., Adachi, H., Katsuno, M., Sobue, G., Taylor, J.P., Sumner, C.J., Fischbeck, K.H., Pennuto, M.
  • Journal Title: Neuron Volume: 63 Pages: 316-328
  • Peer Reviewed
• [Journal Article] TDP-43 Depletion Induces Neuronal Cell Damage through Dysregulation of Rho Family GTPases. (2009)
  • Author(s): Iguchi, Y., Katsuno, M., Niwa, J., Yamada, S., Sone, J., Waza, M., Adachi, H., Tanaka, F., Nagata, K., Arimura, N., Watanabe, T., Kaibuchi, K., Sobue, G.
  • Journal Title: J Biol Chem. Volume: 284 Pages: 22059-22066
  • Peer Reviewed
• [Journal Article] Heat shock proteins in neurodegenerative diseases : Pathogenic roles and therapeutic implications. (2009)
  • Author(s): Adachi, H., Katsuno, M., Waza, M., Minamiyama, M., Tanaka, F., Sobue, G.
  • Journal Title: Int J Hyperthermia Volume: 25 Pages: 647-654
  • 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. Volume: 10 Pages: 1000-1012
• [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 Volume: 29 Pages: 509-516
  • NAID: 10028192075
  • Peer Reviewed
• [Presentation] 球脊髄性筋萎縮症に対する臨床治験の取組 (2010)
  • Author(s): 勝野雅央
  • Organizer: 平成22年度厚生労働科学研究費補助金(難治性疾患克服研究事業)「今後の難病対策に関する研究」シンポジウム
  • Place of Presentation: 東京[招待講演]
  • Year and Date: 2010-08-28
• [Presentation] 球脊髄性筋萎縮症に対する臨床治験の取組 (2010)
  • Author(s): 勝野雅央
  • Organizer: 平成22年度厚生労働科学研究費補助金(難治性疾患克服研究事業)「今後の難病対策に関する研究」シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2010-08-28
• [Presentation] Disrupted TGF-υ signaling in spinal and bulbar muscular atrophy. (2010)
  • Author(s): Katsuno M, Adachi H, Minamiyama M, Doi H, Kondo N, Matsumoto S, Miyazaki Y, Banno H, Suzuki K, Tanaka F, Sobue G.
  • Organizer: 21st International Symposium on ALS/MND.
  • Place of Presentation: Orlando, USA
• [Presentation] A peony extract alleviates polyglutamine-mediated motor neuron disease. (2010)
  • Author(s): Adachi H, Tohnai G, Katsuno M, Minamiyama M, Doi H, Matsumoto S, Kondo N, Miyazaki Y, Tanaka F, Sobue G.
  • Organizer: Neuroscience 2010
  • Place of Presentation: San Diego, USA
• [Presentation] Oxidative stress induces TDP-43 modification, recapitulating its pathological feature. (2010)
  • Author(s): Iguchi Y, Katsuno M, Takagi S, Sobue G.
  • Organizer: Neuroscience 2010
  • Place of Presentation: San Diego, USA
• [Presentation] Videofluorography in spinal and bulbar muscular atrophy (SBMA). (2010)
  • Author(s): Banno H, Katsuno M, Suzuki K, Tanaka S, Kawashima M, Suga N, Hashizume A, Fujimoto Y.Sobue G.
  • Organizer: 62nd American Academy of Neurology Annual Meeting
  • Place of Presentation: Tronto, Canada
• [Presentation] 運動ニューロン変性におけるTGF-βシグナルの役割 (2010)
  • Author(s): 勝野雅央, 足立弘明, 南山誠, 土井英樹, 近藤直英, 松本慎二郎, 田中章景, 祖父江元
  • Organizer: 第6回宮崎サイエンスキャンプ
  • Place of Presentation: 宮崎[招待講演]
• [Presentation] Disrupted TGF-beta signaling in spinal and bulbar muscular atrophy. (2010)
  • Author(s): Katsuno M, Adachi H, Minamiyama M, Doi H, Kondo N, Matsumoto S, Miyazaki Y, Banno H, Suzuki K, Tanaka F, Sobue G.
  • Organizer: 21st International Symposium on ALS/MND.
  • Place of Presentation: Orlando, USA
• [Presentation] A peony extract alleviates polyglutamine-mediated motor neuron disease (2010)
  • Author(s): Adachi H, Tohnai G, Katsuno M, Minamiyama M, Doi H, Matsumoto S, Kondo N, Miyazaki Y, Tanaka F, Sobue G.
  • Organizer: Neuroscience 2010
  • Place of Presentation: San Diego, USA
• [Presentation] 球脊髄性筋萎縮症(SBMA)の心筋におけるNaチャンネル機能の解析 (2010)
  • Author(s): 勝野雅央、坂野晴彦、鈴木啓介、須賀徳明、橋詰淳、足立弘明、堀江稔、松浦博、田中章景、祖父江元
  • Organizer: 第51回日本神経学会総会
  • Place of Presentation: 東京
• [Presentation] 運動ニューロン変性におけるTGF-betaシグナルの役割 (2010)
  • Author(s): 勝野雅央, 足立弘明, 南山誠, 土井英樹, 近藤直英, 松本慎二郎, 田中章景, 祖父江元
  • Organizer: 第6回宮崎サイエンスキャンプ
  • Place of Presentation: 宮崎
• [Presentation] 神経変性疾患に対する分子標的治療の開発と応用-球脊髄性筋萎縮症(SBMA)を中心に (2009)
  • Author(s): 勝野雅央
  • Organizer: 国立循環器病センターセミナー
  • Place of Presentation: 大阪
  • Year and Date: 2009-10-30
• [Presentation] 医師主導臨床試験の方法論,神経変性疾患の臨床試験の実施経験から (2009)
  • Author(s): 勝野雅央
  • Organizer: 医薬経済学教育研究プログラム第3回シンポジウム「患者アウトカム研究への期待と課題」
  • Place of Presentation: 東京
  • Year and Date: 2009-09-05
• [Presentation] 球脊髄性筋萎縮症に対する分子治療 (2009)
  • Author(s): 勝野雅央
  • Organizer: 第50回日本神経学会総会シンポジウム「ポリグルタミン病への分子生物学的アプローチ」
  • Place of Presentation: 仙台
  • Year and Date: 2009-05-22
• [Presentation] TDP-43 depletion induces neuronal cell damage through dysregulation of Rho family GTPases. (2009)
  • Author(s): Iguchi Y, Katsuno M, Niwa J, Yamada S, Sone J, Waza M, Adachi H, Tanaka F, Nagata K, Arimura N, Watanabe T, Kaibuchi K, Sobue G.
  • Organizer: Neuroscience 2009
  • Place of Presentation: Chicago, USA
• [Presentation] 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.
  • Organizer: 61st American Academy of Neurology Annual Meeting
  • Place of Presentation: Seattle, USA
• [Presentation] 球脊髄性筋萎縮症(SBMA)におけるナトリウムチャンネルの発現異常. (2009)
  • Author(s): 勝野雅央、足立弘明、南山誠、土井英樹、近藤直英、松本慎二郎、坂野晴彦、鈴木啓介、田中章景、祖父江元
  • Organizer: Neuro2010
  • Place of Presentation: 神戸
• [Presentation] TDP-43 depletion induces neuronal cell damage through dysregulation of Rho family GTPases.. (2009)
  • Author(s): Iguchi, Y., Katsuno, M., Niwa, J., Yamada, S., Sone, J., Waza, M., Adachi, H., Tanaka, F., Nagata, K., Arimura, N., Watanabe, T., Kaibuchi, K., Sobue, G.
  • Organizer: Neuroscience 2009
  • Place of Presentation: Chicago, USA
• [Presentation] ポリグルタミン病におけるTGF-betaシグナルの異常 (2009)
  • Author(s): 勝野雅央, 足立弘明, 南山誠, 和座雅浩, 徳井啓介, 土井英樹, 田中章景, 祖父江元
  • Organizer: 第32回日本神経科学大会
  • Place of Presentation: 名古屋
• [Presentation] ポリグルタミン病におけるTGF-betaシグナル異常 (2009)
  • Author(s): 勝野雅央, 足立弘明, 南山誠, 和座雅浩, 徳井啓介, 土井英樹, 坂野晴彦, 鈴木啓介, 竹内優, 川島基, 須賀徳明, 祖父江元
  • Organizer: 第50回日本神経学会総会
  • Place of Presentation: 仙台
• [Book] In Diseases of DNA Repair.(Shamim I.Ahmad ed.)(Clinical features and Molecular Mechanisms of spinal and bulbar muscular atrophy (SBMA).), Austin, USA (2010)
  • Author(s): Katsuno M, Banno H, Suzuki K, Adachi H, Tanaka F, Sobue G.
  • Publisher: Landes Bioscience
• [Book] Clinical features and Molecular Mechanisms of spinal and bulbar muscularatrophy (SBMA). In Diseases of DNA Repair. Shamim I.Ahmad ed. (2009)
  • Author(s): Katsuno, M., Banno, H., Suzuki, K., Adachi, H., Tanaka, F., Sobue, G.
  • Total Pages: 256
  • Publisher: Landes Bioscience
• [Patent(Industrial Property Rights)] 球脊髄性筋萎縮症治療薬 (2009)
  • Inventor(s): 祖父江元・南山誠・勝野雅央
  • Industrial Property Number: 2009-277101
  • Filing Date: 2009-12-05