Development of Molecular Targeted Disease Modifying Therapy for Polyglutamine Diseases

2013 Fiscal Year Final Research Report

• Project/Area Number: 21229011
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: SOBUE Gen 名古屋大学, 医学(系)研究科(研究院), 教授 (20148315)
• Co-Investigator(Kenkyū-buntansha): TANAKA Fumiaki 横浜市立大学, 医学研究科, 教授 (30378012) ; ADACHI Hiroaki 名古屋大学, 医学系研究科, 寄附講座准教授 (40432257) ; KATSUNO Masahisa 名古屋大学, 医学系研究科, 准教授 (50402566) ; IIJIMA Masahiro 名古屋大学, 医学系研究科, 寄附講座講師 (40437041) ; KOIKE Haruki 名古屋大学, 医学部附属病院, 病院講師 (80378174)
• Co-Investigator(Renkei-kenkyūsha): OKADA Youhei 慶應義塾大学, 医学部, 講師 (30383714) ; OKANO Hideyuki 慶應義塾大学, 医学部, 教授 (60160694) ; TANAKA Keiji 東京都医学総合研究所, 所長 (10108871)
• Project Period (FY): 2009-05-11 – 2014-03-31
• Keywords: ポリグルタミン病 / 球脊髄性筋萎縮症 / 神経変性 / 細胞周期 / JNK

Research Abstract

Spinal and bulbar muscular atrophy (SBMA)is a motor neuron disease caused by an expansion of CAG trinucleotide expansion with in the androgen receptor (AR) gene. Nuclear accumulation of mutant AR triggers the degeneration of motor neurons in SBMA. Our results indicate that autophagy plays a protective role in SBMA, and that a small compound activating both molecular chaperones and autophagy suppresses the motor neuron degeneration in this disease. We also demonstrated that exogenous supplementation of miRNA that is up-regulated in SBMA mice attenuates mutant AR-mediated motor neuron degeneration.

Research Products

• [Journal Article] Anti-androgen flutamide protects male mice from androgen-dependent toxicity in three models of spinal bulbar muscular atrophy (2014)
  • Author(s): Renier KJ, Troxell-Smith SM, Johansen JA, Katsuno M, Adachi H, Sobue G, Chua JP, Sun Kim H, Lieberman AP, Breedlove SM, Jordan CL
  • Journal Title: Endocrinology Volume: (in press)
  • Peer Reviewed
• [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] 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)
  • DOI: 10.1093/hmg/ddt527
  • 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 Pages: 255-262
  • DOI: 10.1212/WNL.0000000000000041
  • 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 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 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 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 Pages: 1405
  • DOI: 10.1038/ncomms2417
  • Peer Reviewed
• [Journal Article] IGF-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy (2012)
  • Author(s): Rinaldi C, Bott L, Chen K, Harmison G, Katsuno M, Sobue G, Pennuto M, Fischbeck KH
  • Journal Title: Mol Med Volume: 18 Pages: 1261-1268
  • DOI: 10.2119/molmed.2012.00271
  • Peer Reviewed
• [Journal Article] Viral delivery of miR-196a ameliorates the SBMA phenotype via the silencing of CELF2 (2012)
  • Author(s): Miyazaki Y, Adachi H, Katsuno M, Minamiyama M, Jiang YM, Huang Z, Doi H, Matsumoto S, Kondo N, Iida M, Tohnai G, Tanaka F, Muramatsu S, Sobue G
  • Journal Title: Nat Med Volume: 18 Pages: 1136-1141
  • DOI: 10.1038/nm.2791
  • Peer Reviewed
• [Journal Article] Naratriptan mitigates CGRP1-associated motor neuron degeneration caused by expanded polyglutamine (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
  • Journal Title: Nat Med Volume: 18 Pages: 1531-1538
  • DOI: 10.1038/nm.2932
  • 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 Pages: 246-256
  • DOI: 10.1016/j.pneurobio.2012.05.007
  • 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
  • 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 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 Pages: 329-335
  • DOI: 10.1136/jnnp-2011-301307
  • Peer Reviewed
• [Journal Article] Disruption of axonal transport in motor neuron diseases (2012)
  • Author(s): Ikenaka K, Katsuno M, Kawai K, Ishigaki S, Tanaka F, Sobue G
  • Journal Title: Int J Mol Sci Volume: 13 Pages: 1225-1238
  • DOI: 10.3390/ijms1301122
  • Peer Reviewed
• [Journal Article] Macroautophagy is regulated by the UPR-mediator CHOP and accentuates the phenotype of SBMA mice (2011)
  • Author(s): Yu Z, Wang AM, Adachi H, Katsuno M, Sobue G, Yue Z, Robins DM, Lieberman AP
  • Journal Title: PLoS Genet Volume: 7 Pages: e1002321
  • DOI: 10.1371/journal.pgen.1002321
  • 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: 5702-5712
  • DOI: 10.1523/JNEUROSCI.0388-10.2010
  • Peer Reviewed
• [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
  • Year and Date: 20131109-13
• [Presentation] What can we learn from Kennedy's disease for amyotrophic lateral sclerosis/motor neuron disease (2013)
  • Author(s): Sobue G
  • Organizer: World Congress of Neurology 2013
  • Place of Presentation: Vienna
  • Year and Date: 20130921-26
• [Presentation] Molecular targeted therapy for spinal and bulbar muscular atrophy (2013)
  • Author(s): Sobue G
  • Organizer: Gordon Research Conference CAG Triplet Repeat Disorders
  • Place of Presentation: Waterville Valley, USA
  • Year and Date: 20130623-28
• [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
  • Year and Date: 20121205-07
• [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
  • Year and Date: 20121013-17
• [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
  • Year and Date: 20121013-17
• [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
  • Year and Date: 20121013-17
• [Presentation] Molecular pathogenesis and translational research in spinal and bulbar muscular atrophy (SBMA) (2011)
  • Author(s): Sobue G
  • Organizer: 22th International Symposium on ALS/MND
  • Place of Presentation: Sydney, Australia
  • Year and Date: 20111130-1202
• [Presentation] A peony extract enhances protein degradation systems and exerts therapeutic effects in the polyglutamine-mediated motor neuron disease (2011)
  • Author(s): Adachi H, Tohnai G, Katsuno M, Minamiyama M, Doi H, Matsumoto S, Kondo N, Miyazaki Y, Tanaka F, Ohtsuka K, Sobue G
  • Organizer: Neuroscience 2011
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20111111-16
• [Presentation] Heat shock factor-1(Hsf-1) influences distribution of pathogenic androgen receptor aggregations in model mouse of spinal and bulbar muscular atrophy (SBMA) (2011)
  • Author(s): Kondo N, Katsuno M, Adachi H, Minamiyama M, Doi H, Matsumoto S-J, Miyazaki Y, Tanaka F, Sobue G
  • Organizer: Gordon conference on CAG triplet repeat disorders
  • Place of Presentation: Il Ciocco, Italy
  • Year and Date: 20110605-10
• [Presentation] Cell cycle dysregulation in spinal and bulbar muscular atrophy (SBMA) (2011)
  • Author(s): Katsuno M, Adachi H, Kondo N, Minamiyama M, Doi H, Matsumoto S-J, Miyazaki Y, Tanaka F, Sobue G
  • Organizer: Gordon conference on CAG triplet repeat disorders
  • Place of Presentation: Il Ciocco, Italy
  • Year and Date: 20110605-10