Elucidation of activity-dependent synapse pathology and development of therapy for spinal and bulbar muscular atrophy

• Project/Area Number: 24659428
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: KATSUNO MASAHISA 名古屋大学, 医学(系)研究科(研究院), 准教授 (50402566)
• Co-Investigator(Kenkyū-buntansha): ADACHI Hiroaki 名古屋大学, 医学系研究科, 寄附講座准教授 (40432257)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 運動ニューロン疾患 / シナプス / 神経筋接合部 / 球脊髄性筋萎縮症 / 神経変性 / 運動ニューロン / マイクロアレイ / 骨格筋 / 神経変性疾患

Research Abstract

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease caused by the expansion of a trinucleotide CAG repeat in androgen receptor (AR).Recent studies suggest that synaptic dysfunction is an early molecular event in the pathogenesis of various neurodegenerative disorders. In this study, we investigated the synapse pathology in a mouse model of SBMA using immunohistochemistry and microarray analysis. Our results showed that neuromuscular junctions of SBMA mice are denervated at pre-symptomatic stage of the disease. The gene expression analysis identified down-regulated genes that have functions including ion binding.

Research Products

• [Journal Article] Brugada syndrome in spinal and bulbar muscular atrophy. (2014)
  • Author(s): Araki A, Katsuno M, Suzuki K, Banno H, Suga N, Hashizume A, Mano T, Hijikata Y, Nakatsuji H, Watanabe H, Yamamoto M, Makiyama T, Ohno S, Fukuyama M, Morimoto S, Horie M, Sobue G
  • Journal Title: Neurology Volume: 82 Issue: 20 Pages: 1813-1821
  • DOI: 10.1212/wnl.0000000000000434
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Paeoniflorin eliminates a mutant AR via NF-YA-dependent proteolysis in spinal and bulbar muscular atrophy (2014)
  • Author(s): Tohnai G, Adachi H, Katsuno M, Doi H, Matsumoto S, Kondo N, Miyazaki Y, Iida M, Nakatsuji H, Qiang Q, Ding Y, Watanabe H, Yamamoto M, Ohtsuka K, Sobue G.
  • Journal Title: Hum Mol Genet Volume: (in press)
  • Peer Reviewed
• [Journal Article] Tongue pressure as a novel biomarker of spinal and bulbar muscular atrophy (SBMA) (2014)
  • Author(s): Mano T, Katsuno M, Banno H, Suzuki K, Suga N, Hashizume A, Araki A, Watanabe H, Tanaka S, Yamamoto M, Sobue G
  • Journal Title: Neurology Volume: 82 Issue: 3 Pages: 255-262
  • DOI: 10.1212/wnl.0000000000000041
  • Peer Reviewed
• [Journal Article] Transcriptional activation of TFEB/ZKSCAN3 target genes underlies enhanced autophagy in spinobulbar muscular atrophy (2014)
  • Author(s): Chua JP, Reddy SL, Merry DE, Adachi H, Katsuno M, Sobue G, Robins DM, Lieberman AP
  • Journal Title: Hum Mol Genet Volume: (Epub ahead of print) Issue: 5 Pages: 1376-1386
  • DOI: 10.1093/hmg/ddt527
  • Peer Reviewed
• [Journal Article] p62/SQSTM1 differentially removes the toxic mutant androgen receptor via autophagy and inclusion formation in a spinal and bulbar muscular atrophy mouse model (2013)
  • Author(s): Doi H, Adachi H, Katsuno M, Minamiyama M, Matsumoto S, Kondo N, Miyazaki Y, IidaM,Tohnai G, Qiang Q, Tanaka F, Yanagawa T, WarabiE,Ishii T, Sobue G
  • Journal Title: J Neurosci Volume: 33 Issue: 18 Pages: 7710-7727
  • DOI: 10.1523/jneurosci.3021-12.2013
  • Peer Reviewed
• [Journal Article] Translational research on disease-modifying therapies for neurodegenerative diseases (2013)
  • Author(s): Katsuno M, Watanabe H, Tanaka F, Sobue G
  • Journal Title: Neurology and Clinical Neuroscience Volume: 1 Issue: 1 Pages: 3-10
  • DOI: 10.1002/ncn3.7
  • Peer Reviewed
• [Journal Article] Genistein, a natural product derived from soybeans, ameliorates polyglutamine-mediated motor neuron disease (2013)
  • Author(s): Qiang Q, Adachi H, Huang Z, Jiang YM, Katsuno M, Minamiyama M, Doi H, Matsumoto S, Kondo N, Miyazaki Y, Iida M, Tohnai G, Sobue G
  • Journal Title: J Neurochem Volume: 126 Issue: 1 Pages: 122-130
  • DOI: 10.1111/jnc.12172
  • Peer Reviewed
• [Journal Article] Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration (2013)
  • Author(s): Kondo N, Katsuno M, Adachi H, Minamiyama M, Doi H, Matsumoto S, Miyazaki Y, Iida M, Tohnai G, Nakatsuji H, Ishigaki S, Fujioka Y, Watanabe H, Tanaka F, Nakai A, Sobue G
  • Journal Title: Nat Commun Volume: 4 Issue: 1 Pages: 1405-1405
  • DOI: 10.1038/ncomms2417
  • Peer Reviewed
• [Journal Article] Pathogenesis and therapy of spinal and bulbar muscular atrophy (SBMA) (2012)
  • Author(s): Katsuno M, Tanaka F, Adachi H, Banno H, Suzuki K, Watanabe H, Sobue G
  • Journal Title: Prog Neurobiol Volume: 99 Issue: 3 Pages: 246-256
  • DOI: 10.1016/j.pneurobio.2012.05.007
  • Peer Reviewed
• [Journal Article] Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy (SBMA). (2012)
  • Author(s): Banno, H., Katsuno, M., Suzuki, K., Tanaka, F., Sobue, G.
  • Journal Title: Cell Tissue Res Volume: 349 Issue: 1 Pages: 313-320
  • DOI: 10.1007/s00441-012-1377-9
  • Peer Reviewed
• [Journal Article] Current status of treatment of spinal and bulbar muscular atrophy (2012)
  • Author(s): Tanaka F, Katsuno M, Banno H, Suzuki K, Adachi H, Sobue G
  • Journal Title: Neural Plast Volume: 2012 Pages: 369284-369284
  • DOI: 10.1155/2012/369284
  • Peer Reviewed
• [Journal Article] Molecular pathophysiology and disease-Modifying therapies for spinal and bulbar muscular atrophy (2012)
  • Author(s): Katsuno M, Banno H, Suzuki K, Adachi H, Tanaka F, Sobue G
  • Journal Title: Arch Neurol Volume: 69 Issue: 4 Pages: 436-440
  • DOI: 10.1001/archneurol.2011.2308
  • Peer Reviewed
• [Journal Article] Perspectives on molecular targeted therapies and clinical trials for neurodegenerative diseases (2012)
  • Author(s): Katsuno M, Tanaka F, Sobue G
  • Journal Title: J Neurol Neurosurg Psychiatry Volume: 83 Issue: 3 Pages: 329-335
  • DOI: 10.1136/jnnp-2011-301307
  • Peer Reviewed
• [Presentation] Pathogenesis of selective neurodegeneration in polyglutamine-mediated motor neuron disease (2014)
  • Author(s): Katsuno M, Sobue G.
  • Organizer: International symposium. New Frontier of Molecular Neuropathology 2014
  • Place of Presentation: Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
• [Presentation] Neurobiological Study of Postmortem Brain from Brain Bank : for the study of spinal disorders (2013)
  • Author(s): Katsuno M.
  • Organizer: Neuro2013
  • Place of Presentation: Kyoto International Conference Center, Kyoto City, Japan
  • Year and Date: 2013-06-22
• [Presentation] 運動ニューロン疾患に対する分子標的治療法の開発 (2013)
  • Author(s): 勝野雅央
  • Organizer: 第4回神経科学と構造生物学の融合研究会
  • Place of Presentation: 自然科学研究機構岡崎コンファレンスセンター,岡崎市
• [Presentation] Genistein, a natural product derived from soybeans (2013)
  • Author(s): Adachi H, Qiang Q, Hunag Z, Jinag YM, Katsuno M, Kondo N, Miyazaki Y, Iida M, Tohnai G, Nakatsuji H, Sobue G.
  • Organizer: ameliorates polyglutamine-mediated motor neuron disease. Neuroscience 2013
  • Place of Presentation: San Diego, USA
• [Presentation] FUS regulates alternative splicing patterns of Mapt by cooperating with PSF/SFPQ : a novel link between FUS and Tau in the pathogenesis of ALS and FTLD (2013)
  • Author(s): Ishigaki S, Fujioka Y, Udagawa T, Honda D, Katsuno M, Sobue G.
  • Organizer: Neuroscience 2013
  • Place of Presentation: San Diego, USA
• [Presentation] FUS-regulated region- and cell-type-specific transcriptome is associated with cell selectivity in ALS/FTLD (2013)
  • Author(s): Fujioka Y, Ishigaki S, Udagawa T, Honda D, Katsuno M, Sobue G.
  • Organizer: Neuroscience 2013
  • Place of Presentation: San Diego, USA
• [Presentation] Deficits in brain-derived neurotrophic factor may underlie motor dysfunction in spinal bulbar muscular atrophy. (2013)
  • Author(s): Hlievski K, Henley CL, Fu M, Katsuno M, Adachi H, Sobue G, Breedlove SM, Jordan CL.
  • Organizer: Neuroscience 2013
  • Place of Presentation: San Diego, USA
• [Presentation] Genistein, a natural product derived from soybeans, ameliorates polyglutamine-mediated motor neuron disease. (2013)
  • Author(s): Adachi H, Qiang Q, Hunag Z, Jinag YM, Katsuno M, Kondo N, Miyazaki Y, Iida M, Tohnai G, Nakatsuji H, Sobue G.
  • Organizer: Neuroscience 2013
  • Place of Presentation: San Diego, USA
• [Presentation] 運動ニューロンの老化と変性 (2012)
  • Author(s): 勝野雅央
  • Organizer: 第34回日本生物学的精神医学会シンポジウム『老いを科学する―神経変性の視点から』
  • Place of Presentation: 神戸国際会議場,神戸市
  • Year and Date: 2012-09-29
• [Presentation] Molecular pathogenesis and therapy of polyglutamine-induced motor neuron degeneration (2012)
  • Author(s): Katsuno M, Adachi H, Minamiyama M, Doi H, Kondo N, Miyazaki Y, Iida M, Tanaka F, Sobue G.
  • Organizer: 35th Annual Meeting of the Japan Neuroscience Society
  • Place of Presentation: Nagoya Congress Center, Nagoya City, Japan
  • Year and Date: 2012-09-21
• [Presentation] Cell cycle dysregulation in motor neurons of spinal and bulbar muscular atrophy (SBMA) (2012)
  • Author(s): Katsuno M, Adachi H, Kondo N, Minamiyama M, Doi H, Matsumoto S, Miyazaki Y, Iida M, Nakatsuji H, Tanaka F, Sobue G.
  • Organizer: 23rd International Symposium on ALS/MND
  • Place of Presentation: Chicago, USA
• [Presentation] Loss of TDP-43 results in age-dependent progressive motor impairment and neuropathological alterations, mimicking motor neuron disease (2012)
  • Author(s): Iguchi Y, Katsuno M, Yamanaka K, Takahashi R, Misawa H, Sasaki S, Tanaka F, Sobue G.
  • Organizer: 23rd International Symposium on ALS/MND
  • Place of Presentation: Chicago, USA
• [Presentation] Longitudinal changes of outcome measures in spinal and bulbar muscular atrophy (2012)
  • Author(s): Hashizume A, Katsuno M, Banno H, Suzuki K, Suga N, Mano T, Atsuta N, Oe H, Watanabe H, Tanaka F, SobueG.
  • Organizer: 23rd International Symposium on ALS/MND
  • Place of Presentation: Chicago, USA
• [Presentation] Comparison of Fus-regulating gene expression and alternative splicing profiles among different cell lineages in the central nervous system (2012)
  • Author(s): Ishigaki S, Fujioka Y, Masuda A, Iguchi Y, Katsuno M, Ohno K, Sobue G.
  • Organizer: Neuroscience 2012
  • Place of Presentation: New Orleans, USA
• [Presentation] p62/SQSTM1 removes toxic mutant androgen receptor in spinal bulbar muscular atrophy model mouse (2012)
  • Author(s): Adachi H, Doi H, Katsuno M, Matsumoto S, Kondo N, Miyazaki Y, Tohnai G, Iida M, Tanaka F, Sobue G.
  • Organizer: Neuroscience 2012
  • Place of Presentation: New Orleans, USA
• [Presentation] Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2 (2012)
  • Author(s): Miyazaki Y, Adachi H, Katsuno M, Tanaka F, Muramatsu SI, Sobue G.
  • Organizer: Neuroscience 2012
  • Place of Presentation: New Orleans, USA
• [Presentation] Naratriptan ameliorates SBMA pathology by the repression of CGRP1-activated JNK pathway (2012)
  • Author(s): Minamiyama M, Katsuno M, Adachi H, Doi H, Kondo N, Iida M, Ishigaki S, Fujioka Y, Matsumoto S, Miyazaki Y, Tanaka F, Kurihara H, Sobue G.
  • Organizer: Neuroscience 2012
  • Place of Presentation: New Orleans, USA
• [Presentation] CGRP1 is the new therapeutic target for SBMA (Spinal and Bulbar Muscular Atrophy) (2012)
  • Author(s): Minamiyama M, Katsuno M, Adachi H, Doi H, Kondo N, Iida M, Ishigaki S, Fujioka Y, Matsumoto S, Miyazaki Y, Tanaka F, Kurihara H, Sobue G.
  • Organizer: 11th Biennial Meeting of the Asian Pacific Society for Neurochemistry
  • Place of Presentation: Kobe International Conference Center, Kobe, Japan
• [Presentation] Muscle dysfunction may underlie androgen-dependent motor dysfunction in two mouse models of SBMA. (2012)
  • Author(s): Oki K, Adachi H, Katsuno M, Breedlove M, Sobue G. Wiseman RW, Jordan CL.
  • Organizer: Neuroscience 2012
  • Place of Presentation: New Orleans, USA
• [Presentation] Neurobiological Study of Postmortem Brain from Brain Bank: for the study of spinal disorders.
  • Author(s): Katsuno M
  • Organizer: Neuro2013
  • Place of Presentation: 国立京都国際会館、京都市
  • Invited
• [Presentation] 運動ニューロンの老化と変性.
  • Author(s): 勝野雅央.
  • Organizer: 第34回日本生物学的精神医学会シンポジウム『老いを科学する―神経変性の視点から』
  • Place of Presentation: 神戸国際会議場（神戸）
  • Invited