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

脊髓和延髓肌萎缩症(SBMA)是一种成人起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)基因第一外显子中三核苷酸CAG重复序列的扩展，该外显子编码多谷氨酰胺(PolyQ)区。CAG重复长度与SBMA的严重程度相关。身体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内的弥漫性聚集是SBMA的基本神经病理特征，其程度与CAG重复长度密切相关。因此，突变型AR的弥漫性核积聚可能是SBMA的重要致病步骤。我们建立了两种SBMA小鼠模型。其中，由鸡(3-肌动蛋白启动子)驱动的携带包含97个CAG的全长AR的转基因小鼠模型显示出进行性运动损伤和突变AR的核积聚。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，显着地阻止了雄性TG小鼠的表型表达。相比之下，雌性转基因小鼠服用睾丸素后症状显著恶化。亮丙瑞林是一种LHRH激动剂，可以减少睾丸释放睾酮，抑制突变AR的核积累，导致挽救雄性SBMA小鼠的运动功能障碍。我们的研究还指出了几种治疗SBMA的候选药物。热休克蛋白(HSP)的遗传过表达通过改善突变型AR的构象变化来改善SBMA小鼠模型中的神经变性。组蛋白脱乙酰酶抑制剂丁酸钠可改善SBMA小鼠模型的神经功能障碍，尽管其治疗作用的剂量范围较窄。

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.