Development of therapy targeting dysregulation of cell cycle and JNK pathway in polyglutamine diseases

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390230
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• 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): SOBUE Gen 名古屋大学, 医学系研究科, 教授 (20148315) ; 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)
• Project Period (FY): 2011-04-01 – 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

Polyglutamine diseases are a group of hereditary neurodegenerative disorders caused by an expansion of genomic CAG trinucleotide expansion. Intra-neuronal accumulation of causative protein is construed as a pivotal molecular event in the pathogenesis of polyglutamine diseases. Our study demonstrated that dysregulation of cell cycle and abnormal activation of JNK pathway underlie the motor neuron degeneration in spinal and bulbar muscular atrophy (SBMA). We also showed that pharmacological suppression of JNK ameliorates polyglutamine-mediated neurodegeneration in SBMA.

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
  • 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): DoiH, AdachiH, KatsunoM, MinamiyamaM, MatsumotoS, KondoN, MiyazakiY, IidaM, TohnaiG, QiangQ, TanakaF, YanagawaT, WarabiE, IshiiT, SobueG
  • Journal Title: J Neurosci Volume: 33 Pages: 7710-7727
  • DOI: 10.1523/JNEUROSCI.3021-12.2013
  • 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] 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] 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] 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
• [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
  • Year and Date: 20140316-17
• [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] 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] 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] 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
• [Presentation] Elucidation of neuronal death signaling pathways and development of disease-modifying therapies for Kennedy' s disease (2011)
  • Author(s): Katsuno M
  • Organizer: Kennedy' s Disease Association 2011 Annual Conference and Education Symposium
  • Place of Presentation: Coarsegold, USA
  • Year and Date: 2011-11-11