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

2010 Fiscal Year Final Research Report

• 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
• Keywords: ポリグルタミン病 / 運動ニューロン / TGF-βシグナル

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 Pages: e12922
• [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] 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
• [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
  • Year and Date: 20101211-20101213
• [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
  • Year and Date: 20101113-20101117
• [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
  • Year and Date: 20101113-20101117
• [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
  • Year and Date: 20100410-20100417
• [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]
  • Year and Date: 20100226-20100228
• [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] 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
  • Year and Date: 20091017-20091021
• [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
  • Year and Date: 20090425-20090502
• [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.
  • Total Pages: 64-74
  • Publisher: Landes Bioscience