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

阐明脊髓和延髓肌萎缩症中神经元细胞死亡的分子机制

基本信息

  • 批准号:
    12210010
  • 负责人:
  • 金额:
    $ 69.7万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research on Priority Areas
  • 财政年份:
    2000
  • 资助国家:
    日本
  • 起止时间:
    2000 至 2004
  • 项目状态:
    已结题

项目摘要

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.
脊髓延髓肌萎缩症(SBMA)是一种成年发病的运动神经元疾病,只影响男性。SBMA的分子基础是雄激素受体(AR)基因第一外显子中三核苷酸CAG重复序列的扩增,该基因编码多聚谷氨酰胺(polyQ)序列。CAG重复序列的长度与SBMA的严重程度相关。尸检标本的免疫组化分析表明,突变型AR在脊髓运动神经元核内的弥漫性积聚是SBMA的基本神经病理特征,其程度与CAG重复序列长度密切相关。因此,突变体AR在细胞核内的弥散性积聚可能是SBMA的关键致病步骤。我们建立了两种SBMA小鼠模型。其中,一个转基因小鼠模型携带全长AR含有97个CAG驱动的鸡β-肌动蛋白启动子显示进行性运动障碍和突变体AR的核积累。这些神经学表型在雄性小鼠中是毁灭性的,但在雌性小鼠中没有观察到或严重得多。手术去势通过减少突变体AR的核积累而显著防止雄性Tg小鼠中的表型表达。与此相反,雌性Tg小鼠表现出显著恶化的症状睾酮管理。亮丙瑞林是一种LHRH激动剂,可减少睾丸中的睾酮释放,抑制突变型AR的核蓄积,从而挽救雄性SBMA小鼠的运动功能障碍。我们的研究还表明了SBMA的几种候选治疗药物。在SBMA小鼠模型中,热休克蛋白(HSP)的基因过表达通过改善突变型AR的构象改变来改善神经变性。口服丁酸钠(一种组蛋白去乙酰化酶抑制剂)可改善SBMA小鼠模型的神经功能障碍,尽管其治疗效果在较窄的剂量范围内观察到。

项目成果

期刊论文数量(180)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
CREB-binding protein sequestration by expanded polyglutamine
  • DOI:
    10.1093/hmg/9.14.2197
  • 发表时间:
    2000-09-01
  • 期刊:
  • 影响因子:
    3.5
  • 作者:
    McCampbell, A;Taylor, JP;Fischbeck, KH
  • 通讯作者:
    Fischbeck, KH
Takeuchi H: "Immunoglobulin therapy for idiopathic chronic sensory ataxic neuropathy."Neurology. 54. 1008-1010 (2000)
Takeuchi H:“免疫球蛋白治疗特发性慢性感觉共济失调神经病。”神经病学。
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Watanabe H: "Differential somatic CAG repeat instability in variable brain cell lineage in dentatorubral pallidoluysian atrophy (DRPLA): a laser-captured microdissection (LCM)-based analysis."Hum.Genet.. 107. 452-457 (2000)
Watanabe H:“齿状核红斑苍白卢伊萎缩症 (DRPLA) 中可变脑细胞谱系的差异体细胞 CAG 重复不稳定性:基于激光捕获显微切割 (LCM) 的分析。”Hum.Genet.. 107. 452-457 (2000)
  • DOI:
  • 发表时间:
  • 期刊:
  • 影响因子:
    0
  • 作者:
  • 通讯作者:
Dorfin ubiquitylates mutant SOD1 and prevents mutant SOD1-mediated neurotoxicity
  • DOI:
    10.1074/jbc.m206559200
  • 发表时间:
    2002-09-27
  • 期刊:
  • 影响因子:
    4.8
  • 作者:
    Niwa, J;Ishigaki, S;Sobue, G
  • 通讯作者:
    Sobue, G
Dorfin prevents cell death by reducing mitochondrial localiaing mutant superoxide dismutase 1 in a neuronal cell model of familial amyotrophic lateral sclerosis.
在家族性肌萎缩侧索硬化症的神经元细胞模型中,Dorfin 通过减少线粒体定位突变型超氧化物歧化酶 1 来防止细胞死亡。
  • DOI:
  • 发表时间:
    2004
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Takehara;K.;et al.;Takeuchi H
  • 通讯作者:
    Takeuchi H
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SOBUE Gen其他文献

SOBUE Gen的其他文献

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{{ truncateString('SOBUE Gen', 18)}}的其他基金

Therapeutic strategy of neurodegenerative disease using microRNA
利用microRNA治疗神经退行性疾病的策略
  • 批准号:
    25670418
  • 财政年份:
    2013
  • 资助金额:
    $ 69.7万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Identification of therapeutic targets for ALS by screening for TDP-43 and FUS associated molecules
通过筛选 TDP-43 和 FUS 相关分子鉴定 ALS 治疗靶点
  • 批准号:
    23659452
  • 财政年份:
    2011
  • 资助金额:
    $ 69.7万
  • 项目类别:
    Grant-in-Aid for Challenging Exploratory Research
Development of Molecular Targeted Disease Modifying Therapy for Polyglutamine Diseases
多聚谷氨酰胺疾病分子靶向疾病修饰疗法的发展
  • 批准号:
    21229011
  • 财政年份:
    2009
  • 资助金额:
    $ 69.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (S)
Pathogenesis-based therapy development for polyglutamine diseases
多聚谷氨酰胺疾病的基于发病机制的治疗方法开发
  • 批准号:
    19209033
  • 财政年份:
    2007
  • 资助金额:
    $ 69.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Treatment of polyglutamine disease using small molecular compound
小分子化合物治疗多聚谷氨酰胺病
  • 批准号:
    17209032
  • 财政年份:
    2005
  • 资助金额:
    $ 69.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Development of pathogenesis-based therapy for polyglutamine diseases
多聚谷氨酰胺疾病的基于发病机制的治疗方法的开发
  • 批准号:
    17025020
  • 财政年份:
    2005
  • 资助金额:
    $ 69.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research on Priority Areas
Development of Pathogenesis-based treatment for spinal and bulbar muscular atrophy
脊髓和延髓性肌萎缩症基于发病机制的治疗方法的开发
  • 批准号:
    15209031
  • 财政年份:
    2003
  • 资助金额:
    $ 69.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Neurotrophin and their receptor mRNA expressions in neurodegenerative diseases.
神经营养蛋白及其受体 mRNA 在神经退行性疾病中的表达。
  • 批准号:
    06807059
  • 财政年份:
    1994
  • 资助金额:
    $ 69.7万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)
GENE EXPRESSION AND REGULATION OF NEUROTROPHINS AND THEIR RECEPTORS IN PERIPHERAL NEUROPATHIES
周围神经病中神经营养因子及其受体的基因表达和调节
  • 批准号:
    02807085
  • 财政年份:
    1990
  • 资助金额:
    $ 69.7万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)

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Investigating Motor Neuron Disease in Spinocerebellar Ataxia, Type1
研究脊髓小脑共济失调 1 型运动神经元疾病
  • 批准号:
    10733124
  • 财政年份:
    2023
  • 资助金额:
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  • 项目类别:
Unraveling the mechanisms of motor neuron degeneration if Spinocerebellar Ataxia, type 1
揭示 1 型脊髓小脑共济失调运动神经元变性的机制
  • 批准号:
    9757831
  • 财政年份:
    2017
  • 资助金额:
    $ 69.7万
  • 项目类别:
Deconstructing the cellular and molecular basis of SBMA motor neuron disease: From mechanism to therapy
解构 SBMA 运动神经元疾病的细胞和分子基础:从机制到治疗
  • 批准号:
    9535519
  • 财政年份:
    2016
  • 资助金额:
    $ 69.7万
  • 项目类别:
Therapeutic strategy for polyglutamine-mediated motor neuron disease via molecular chaperone-ubiquitin proteasome system
分子伴侣-泛素蛋白酶体系统治疗聚谷氨酰胺介导的运动神经元疾病的策略
  • 批准号:
    20390243
  • 财政年份:
    2008
  • 资助金额:
    $ 69.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Mechanisms of motor neuron toxicity in Kennedy disease
肯尼迪病运动神经元毒性机制
  • 批准号:
    8469101
  • 财政年份:
    2007
  • 资助金额:
    $ 69.7万
  • 项目类别:
Mechanisms of motor neuron toxicity in Kennedy disease
肯尼迪病运动神经元毒性机制
  • 批准号:
    9906923
  • 财政年份:
    2007
  • 资助金额:
    $ 69.7万
  • 项目类别:
Mechanisms of motor neuron toxicity in Kennedy Disease
肯尼迪病运动神经元毒性机制
  • 批准号:
    8027315
  • 财政年份:
    2007
  • 资助金额:
    $ 69.7万
  • 项目类别:
Mechanisms of motor neuron toxicity in Kennedy Disease
肯尼迪病运动神经元毒性机制
  • 批准号:
    7369671
  • 财政年份:
    2007
  • 资助金额:
    $ 69.7万
  • 项目类别:
Mechanisms of motor neuron toxicity in Kennedy disease
肯尼迪病运动神经元毒性机制
  • 批准号:
    8374314
  • 财政年份:
    2007
  • 资助金额:
    $ 69.7万
  • 项目类别:
Mechanisms of motor neuron toxicity in Kennedy Disease
肯尼迪病运动神经元毒性机制
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    7541734
  • 财政年份:
    2007
  • 资助金额:
    $ 69.7万
  • 项目类别:
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