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.

脊柱和鳞茎肌肉萎缩（SBMA）是一种仅影响男性的成人发作的运动神经元疾病。 SBMA的分子基础是雄激素受体（AR）基因的第一个外显子中三核苷酸CAG重复的膨胀，该外显子编码了多谷氨酰胺（Polyq）束。 CAG重复的长度与SBMA的严重程度相关。对载体标本的免疫组织化学分析表明，突变体在脊柱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的弥漫性核积累可能是SBMA中至关重要的致病步骤。我们生成了两个SBMA的鼠标模型。其中，一种携带全长AR的转基因小鼠模型，该模型包含由鸡驱动的97个CAG（3-肌动蛋白启动子显示出进行性运动障碍和突变AR的核积累。这些神经系统表型在雄性小鼠中是毁灭性的，在女性中却没有观察到的核酸症。 AR。与睾丸激素降低了睾丸激动剂，雌激素抑制了睾丸蛋白，抑制了睾丸的核能，抑制了睾丸蛋白，抑制了睾丸的核能，导致雄性小鼠的疾病中的疾病，这是抑制睾丸的核能。（HSP）通过改善SBMA小鼠模型中突变体AR的构象改变来改善神经退行性，这是一种组蛋白脱乙酰基酶抑制剂，导致SBMA小鼠模型中神经功能障碍的改善，尽管它的治疗效应在狭窄的Dose范围内都可以看到。