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

脊髓和球性肌萎缩症（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）基因第一个外显子的三核苷酸CAG重复扩增，该基因编码聚谷氨酰胺（polyQ）通道。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AR在脊髓运动神经元核内弥漫性积累是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AR的弥漫性核积累可能是SBMA的关键致病步骤。我们建立了两种SBMA小鼠模型。其中，携带全长AR的转基因小鼠模型含有97个由鸡3-肌动蛋白启动子驱动的cag，显示进行性运动损伤和突变AR的核积累。这些神经学表型在雄性小鼠中是破坏性的，但在雌性小鼠中没有观察到或远不严重。手术阉割通过减少突变AR的核积累，显著地阻止了雄性Tg小鼠的表型表达。相反，雌性Tg小鼠在给药后表现出显著的症状恶化。Leuprorelin是一种LHRH激动剂，可以减少睾丸激素的释放，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。我们的研究也指出了SBMA的几种候选治疗方法。遗传过表达热休克蛋白（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，但其治疗效果在小剂量范围内可见。

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.