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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。