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2004 Fiscal Year Final Research Report Summary

Elucidation of molecular mechanism of neuronal cell death in spinal and bulbar muscular atrophy

Research Project

Project/Area Number 12210010
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionNagoya University

Principal Investigator

SOBUE Gen  Nagoya Univesity, Department of Neurology, Professor, 大学院医学系研究科, 教授 (20148315)

Co-Investigator(Kenkyū-buntansha) DOYU Manabu  Nagoya Univesity, Department of Neurology, Assistant Professor, 大学院医学系研究科, 助教授 (90293703)
INUKAI Akira  Nagoya Univesity, Department of Neurology, Lecturer, 医学部附属病院, 講師 (30314016)
Project Period (FY) 2000 – 2004
Keywordsneurodegeneration / motor neuron / polyglutamine / andorogen receptor / LHRH analog / histone / heat shock protein
Research Abstract

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease affecting only males. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat in the first exon of the androgen receptor (AR) gene, which encodes the polyglutamine (polyQ) tract. The length of CAG repeat correlates with the severity of SBMA. Immunohistochemical analysis of autopsied specimen demonstrates that diffuse accumulation of mutant AR in the nuclei of spinal motor neurons is a fundamental neuropathological feature of SBMA, extent of which closely relates to CAG repeat length. Thus, diffuse nuclear accumulation of mutant AR is likely crucial pathogenic step in SBMA. We generated two mouse models of SBMA. Among these, a transgenic mouse model carrying full-length AR containing 97 CAGs driven by a chicken (3-actin promoter shows progressive motor impairment and nuclear accumulation of mutant AR. These neurological phenotypes were devastating in male mice, but not observed or far less severe in the females. Surgical castration dramatically prevented the phenotypic expression in the male Tg mice by diminishing the nuclear accumulation of mutant AR. In contrast, the female Tg mice demonstrated striking deterioration of symptoms by testosterone administration. Leuprorelin, an LHRH agonist that reduces testosterone release from the testis, suppressed nuclear accumulation of mutant AR, leading to rescue of motor dysfunction in the male SBMA mice. Our studies have also indicated several candidates of therapeutics for SBMA. Genetic overexpression of heat shock protein (HSP) ameliorates neurodegeneration by improving conformational alteration of mutant AR in the mouse model of SBMA. Oral administration of sodium butyrate, a histone deacetylase inhibitor, resulted in improvement of neurological dysfunction in the SBMA mouse model, al though its therapeutic effects were seen in a narrow dose range.

  • Research Products

    (52 results)

All 2005 2004 2003 2002 2001 2000

All Journal Article (50 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] Widespread nuclear and cytoplasmic accumulation of mutant androgen receptor in SBMA patients.2005

    • Author(s)
      Adachi H
    • Journal Title

      Brain 128

      Pages: 659-670

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Gene expression profile of motor neurons in sporadic amyotrophic lateral sclerosis.2005

    • Author(s)
      Jiang YM
    • Journal Title

      Ann Neurol 57

      Pages: 236-251

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Widespread nuclear and cytoplasmic mutant androgen receptor accumulation in spinal and bulbar muscular atrophy.2005

    • Author(s)
      Adachi H
    • Journal Title

      Brain 128

      Pages: 659-670

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Sweet relief for Huntington disease.2004

    • Author(s)
      Katsuno M
    • Journal Title

      Nature Medicine 10

      Pages: 123-124

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Polyglutamine diminishes VEGF : Passage to motor neuron death?2004

    • Author(s)
      Katsuno M
    • Journal Title

      Neuron 41

      Pages: 677-679

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Dorfin prevents cell death by reducing mitochondrial localiaing mutant superoxide dismutase 1 in a neuronal cell model of familial amyotrophic lateral sclerosis.2004

    • Author(s)
      Takeuchi H
    • Journal Title

      J Neurochem 89

      Pages: 64-72

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.2004

    • Author(s)
      Minamiyama M
    • Journal Title

      Hum Mol Genet 13

      Pages: 1183-1192

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Spinal and bulbar muscular atrophy : ligand-dependent pathogenesis and therapeutic perspectives2004

    • Author(s)
      Katsuno M
    • Journal Title

      J Mol Med 82

      Pages: 298-307

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Physical and functional interaction between Dorfin and Valosin-containing protein that are colocalized in ubiquitylated inclusions in neurodegenerative disorders.2004

    • Author(s)
      Ishigaki S
    • Journal Title

      J Biol Chem 279

      Pages: 51376-51385

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Spinal and bulbar muscular atrophy : ligand-dependent pathogenesis and therapeutic perspectives.2004

    • Author(s)
      Katsuno M
    • Journal Title

      J Mol Med 82

      Pages: 298-307

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Dorfin prevents cell death by reducing mitochondrial localizing mutant superoxide dismutase 1 in a neuronal cell model of familial amyotrophic lateral sclerosis.2004

    • Author(s)
      Takeuchi H
    • Journal Title

      J Neurochem 89

      Pages: 64-72

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Sweet relief for Huntington disease.2004

    • Author(s)
      Katsuno M
    • Journal Title

      Nature Med 10

      Pages: 123-124

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Dorfin localizes to Lewy bodies and ubiquitilates synphilin-1.2003

    • Author(s)
      Ito T
    • Journal Title

      J Biol Chem 278

      Pages: 29106-29114

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Hsp105a suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity.2003

    • Author(s)
      Ishihara K
    • Journal Title

      J Biol Chem 278

      Pages: 25143-25150

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Dorfin localizes to the ubiquitylated inclusions in Parkinson's disease, dementia with Lewy bodies, multiple sysytem atrophy, and amyotrophic lateral sclerosis.2003

    • Author(s)
      Hishikawa N
    • Journal Title

      Am J Pathol 163

      Pages: 609-619

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein.2003

    • Author(s)
      Adachi H
    • Journal Title

      J Neurosci 23

      Pages: 2203-2211

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Leuprorelin rescue polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy.2003

    • Author(s)
      Katsuno M
    • Journal Title

      Nature Medicine 9

      Pages: 768-773

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Transgenic mouse models of spinal and bulbar muscular atrophy (SBMA).2003

    • Author(s)
      Katsuno M
    • Journal Title

      Cytogenet Genome Res 100

      Pages: 243-251

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Dorfin localizes to Lewy bodies and ubiquitylates synphilin-1.2003

    • Author(s)
      Ito T
    • Journal Title

      J Biol Chem 278(31)

      Pages: 29106-29114

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Hsp105a suppresses the aggregation of truncated androgen receptor with expanded CAG repeats and cell toxicity.2003

    • Author(s)
      Ishihara K
    • Journal Title

      J Biol Chem 278(27)

      Pages: 25143-25150

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Dorfin localizes to the ubiquitilated inclusions in Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and amyotrophic lateral sclerosis.2003

    • Author(s)
      Hishikawa N
    • Journal Title

      Am J Pathol 163(2)

      Pages: 609-619

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Leuprorelin rescue polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy2003

    • Author(s)
      Katsuno M
    • Journal Title

      Nature Medicine 9(6)

      Pages: 768-773

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Heat shock protein 70 chaperone overexpression ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model by reducing nuclear-localized mutant androgen receptor protein.2003

    • Author(s)
      Adachi H
    • Journal Title

      J Neurosci 23(6)

      Pages: 2203-2211

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Mitochondrial localization of mutant superoxide dismutase 1 triggers caspase-dependent cell death in a cellular model of familial amyotrophic lateral sclerosis.2002

    • Author(s)
      Takeuchi H
    • Journal Title

      J Biol Chem 277

      Pages: 50966-50972

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Differential expression of inflammation-and apoptosis-related genes in spinal cords of a mutant SOD1 trangenic mouse model of familial amyotrophic lateral sclerosis.2002

    • Author(s)
      Yoshihara T
    • Journal Title

      J Neurochem 80

      Pages: 158-167

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] X-linked inhibitor of apoptosis protein is involved in mutant SOD-1 mediated neuronal degeneration.2002

    • Author(s)
      Ishigaki S
    • Journal Title

      J Neurochem 82

      Pages: 576-584

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Teststerone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.2002

    • Author(s)
      Katsuno M
    • Journal Title

      Neuron 35

      Pages: 843-854

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity.2002

    • Author(s)
      Niwa J
    • Journal Title

      J Biol Chem 277

      Pages: 36793-36798

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Differentially expressed genes in sporadic amyotrophic lateral sclerosis spinal cords -screening by molecular indexing and subsequent cDNA microarray analysis.2002

    • Author(s)
      Ishigaki S
    • Journal Title

      FEBS Lett 531

      Pages: 354-358

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] c-Jun N-terminal kinase pathway mediates Lactacustin-induced cell death in a neuronal differentiated Neuro2a cell line.2002

    • Author(s)
      Sang C
    • Journal Title

      Mol Brain Res 108

      Pages: 7-17

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Hsp70 and Hsp40 improve neurite outgrowth and suppress intracytoplasmic aggregate formation in cultured neuronal cells expressing mutant SOD1.2002

    • Author(s)
      Takeuchi H
    • Journal Title

      Brain Res 949

      Pages: 11-22

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mitochondrial localization of mutant superoxide dismutase 1 triggers caspase-dependent cell death in a cellular model of familial amyotrophic lateral sclerosis.2002

    • Author(s)
      Takeuchi H
    • Journal Title

      J Biol Chem 277(52)

      Pages: 50966-50972

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity.2002

    • Author(s)
      Niwa J
    • Journal Title

      J Biol Chem 277(39)

      Pages: 36793-36798

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.2002

    • Author(s)
      Katsuno M
    • Journal Title

      Neuron 35

      Pages: 843-854

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Differential expression of inflammation-and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis.2002

    • Author(s)
      Yoshihara T
    • Journal Title

      J Neurochem 80

      Pages: 158-167

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death.2001

    • Author(s)
      Adachi H
    • Journal Title

      Hum Mol Genet 10

      Pages: 1039-1048

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Differential effects of leukocyte common antigen-related protein on biochemical and biological activities of RET-MEN2A and RET-MEN2B mutant proteins.2001

    • Author(s)
      Qiao S
    • Journal Title

      J Biol Chem 276

      Pages: 9460-9467

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Preserved phosphorylation of RET receptor protein in spinal motor neurons of patients with amyotrophic lateral sclerosis : an immunohistochemical study by a phosphorylation-specific antibody at tyrosine 1062.2001

    • Author(s)
      Yamamoto M
    • Journal Title

      Brain Res 912

      Pages: 89-94

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A novel centrosomal ring-finger protein, dorfin, mediates ubiquitin ligase activity.2001

    • Author(s)
      Niwa J
    • Journal Title

      Biochem Biophys Res Commun 281

      Pages: 706-713

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Gene expression profile in Alzheimer's brain screened by molecular indexing.2001

    • Author(s)
      Doyu M
    • Journal Title

      Brain Res, Mol Brain Res 87

      Pages: 1-11

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Specific bisulfite modification of CTG triplet repeats of the androgen receptor gene, a gene associated with the triplet repeat disease. X-linked spinal and bulbar muscular atrophy (Kennedy disease).2001

    • Author(s)
      Ochi K
    • Journal Title

      Neurosci Res Commun 28

      Pages: 1-11

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A novel missense mutation in the early growth response 2 gene associated with late-onset Charcot-Marie-Tooth disease type 1.2001

    • Author(s)
      Yoshihara T
    • Journal Title

      J Neurol Sci 184

      Pages: 149-153

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Transgenic mice with an expande CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death.2001

    • Author(s)
      Adachi H
    • Journal Title

      Hum Mol Genet 10(10)

      Pages: 1039-1048

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A novel centrosomal RING-finger protein, Dorfin, mediates ubiquitin ligase activity.2001

    • Author(s)
      Niwa J
    • Journal Title

      Biochem Biophys Res Com 281

      Pages: 706-713

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Differential effects of LAR on biochemical and biological activities of RET-MEN2A and RET-MEN2B mutant protein.2001

    • Author(s)
      Qiao S
    • Journal Title

      J Biol Chem 276(12)

      Pages: 9460-9467

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Gene expression profile in Alzheimer's brain screened by molecular indexing.2001

    • Author(s)
      Doyu M
    • Journal Title

      Mol Brain Res 87

      Pages: 1-11

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Hsp70 and Hsp40, suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract.2000

    • Author(s)
      Kobayashi Y
    • Journal Title

      J Biol Chem 275

      Pages: 8772-8778

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Two novel genes, human neugrin and mouse m-neugrin, are upregulated with neuronal differentiation in neuroblastoma cells.2000

    • Author(s)
      Ishigaki S
    • Journal Title

      Biochem Biophys Res Com 279

      Pages: 526-533

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] CREB-binding protein sequestration by expanded polyglutamine.2000

    • Author(s)
      McCampbell A
    • Journal Title

      Hum Mol Genet 9

      Pages: 2197-2202

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Differential somatic CAG repeat instability in variable brain cell lineage in dentatorubral pallidoluysian atrophy (DRPLA) : a laser-captured microdissection (LCM)-based analysis.2000

    • Author(s)
      Watanabe H
    • Journal Title

      Hum Genet 107

      Pages: 452-457

    • Description
      「研究成果報告書概要(和文)」より
  • [Patent(Industrial Property Rights)] 抗ポリグルタミン病剤.2004

    • Inventor(s)
      勝野雅央, 祖父江元
    • Industrial Property Rights Holder
      勝野雅央, 祖父江元
    • Industrial Property Number
      特願2004-246980
    • Filing Date
      20040826出願
    • Description
      「研究成果報告書概要(和文)」より
  • [Patent(Industrial Property Rights)] 球脊髄性筋萎縮症の病態を再現する非ヒト動物、及び球脊髄性筋萎縮症治療剤.2002

    • Inventor(s)
      勝野雅央, 足立弘明, 祖父江元
    • Industrial Property Rights Holder
      勝野雅央, 足立弘明, 祖父江元
    • Industrial Property Number
      特願2002-238599
    • Filing Date
      20020819出願
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2008-05-27  

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