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
- 来源:
- 关键词:
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.
脊髓和延髓肌萎缩症 (SBMA) 是一种成人发病的运动神经元疾病,仅影响男性。 SBMA 的分子基础是雄激素受体 (AR) 基因第一个外显子中三核苷酸 CAG 重复的扩展,该基因编码多聚谷氨酰胺 (polyQ) 区域。 CAG 重复序列的长度与 SBMA 的严重程度相关。尸检标本的免疫组织化学分析表明,突变型 AR 在脊髓运动神经元核中的弥漫性积累是 SBMA 的基本神经病理学特征,其程度与 CAG 重复长度密切相关。因此,突变体 AR 的弥漫核积累可能是 SBMA 的关键致病步骤。我们生成了两种 SBMA 小鼠模型。其中,携带含有 97 个由鸡驱动的 CAG 的全长 AR 的转基因小鼠模型(3-肌动蛋白启动子)显示进行性运动障碍和突变 AR 的核积累。这些神经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远没有那么严重。手术去势通过减少突变 AR 的核积累,显着阻止了雄性 Tg 小鼠的表型表达。 AR。相比之下,雌性 Tg 小鼠在注射睾酮后表现出症状显着恶化。 Leuprorelin 是一种 LHRH 激动剂,可减少睾丸中睾酮的释放,抑制突变 AR 的核积累,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 的几种候选治疗方法。热休克蛋白的基因过度表达 (HSP) 通过改善 SBMA 小鼠模型中突变 AR 的构象改变来改善神经退行性变。口服组蛋白脱乙酰酶抑制剂丁酸钠可改善 SBMA 小鼠模型中的神经功能障碍,尽管其治疗作用在较窄的剂量范围内可见。
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)
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:
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
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.
肌萎缩侧索硬化症患者脊髓运动神经元中 RET 受体蛋白的保留磷酸化:通过酪氨酸 1062 磷酸化特异性抗体进行的免疫组织化学研究。
- DOI:
- 发表时间:2001
- 期刊:
- 影响因子:0
- 作者:Takeuchi;T.;et al.;Yamamoto M
- 通讯作者:Yamamoto M
Hsp70 and Hsp40, suppress aggregate formation and apoptosis in cultured neuronal cells expressing truncated androgen receptor protein with expanded polyglutamine tract.
Hsp70 和 Hsp40 可抑制表达具有扩展的聚谷氨酰胺束的截短雄激素受体蛋白的培养神经元细胞中的聚集体形成和细胞凋亡。
- DOI:
- 发表时间:2000
- 期刊:
- 影响因子:0
- 作者:Uemura;T.;Mori;H.;Mishina;M.;Kobayashi Y
- 通讯作者:Kobayashi Y
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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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