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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：
SOBUE Gen
金额：
$ 69.7万
依托单位：
Nagoya University
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。