Development of Pathogenesis-based treatment for spinal and bulbar muscular atrophy

脊髓延髓肌萎缩症（SBMA）是一种遗传性运动神经元疾病，主要由雄激素受体（AR）基因CAG三核苷酸重复序列扩增引起。SBMA患者脊髓的组织学分析表明，脊髓运动和感觉神经元中突变型AR的弥漫性核积聚程度与CAG重复序列长度密切相关。转基因小鼠SBMA携带全长人AR基因（含97个CAG），表现出明显的性别差异，雄性比雌性更明显。用手术去势或LHRH类似物治疗来剥夺睾丸激素抑制突变型AR蛋白的核积累，从而显著改善SBMA小鼠的神经表型和组织病理学异常。LHRH类似物治疗SBMA患者的临床试验正在进行中，SBMA转基因小鼠与过表达人Hsp 70小鼠杂交，结果显示突变型AR在细胞核中的蓄积受到抑制，运动功能明显改善。Hsp 70不仅抑制突变体AR的聚集，而且促进该蛋白的降解。在SBMA的细胞培养模型中，Hsp 70诱导剂香叶基香叶基丙酮增强了被抑制的突变体AR的核积累，从而减轻了由扩展的聚谷氨酰胺施加的神经毒性。口服GGA可减轻SBMA小鼠神经元功能障碍;口服组蛋白去乙酰化酶抑制剂丁酸钠可上调SBMA小鼠组蛋白乙酰化水平，改善SBMA小鼠表型，但丁酸钠的治疗窗较窄。(266字）

Spinal and bulbar muscular atrophy(SBMA), a hereditary motor neuron disease affecting adult males, is caused by expansion of CAG trinucleotide repeat in the androgen receptor(AR) gene. Histopathological analysis of the spinal cord from SBMA patients demonstrated that the extent of diffuse nuclear accumulation of mutant AR in motor and sensory neurons of the spinal cord was closely related to CAG repeat length. A transgenic mouse model of SBMA carrying full-length human AR gene containing 97 CAGs showed significant sexual differences in phenotypes which was more progressive in males than females. Testosterone deprivation with either surgical castration or LHRH analogue treatment suppressed nuclear accumulation of mutant AR protein and thereby significantly improved neurological phenotypes and histopathological abnormalities in SBMA mice. Clinical trial of LHRH analogue for SBMA patients is currently being conducted.Cross-breeding of SBMA transgenic mice with mice overexpressing human Hsp70 resulted in inhibition of nuclear accumulation of mutant AR as well as marked amelioration of the motor function. Hsp70 did not only inhibit aggregation of mutant AR but also facilitated degradation of this protein. In a cell culture model of SBMA, geranylgeranylacetone, Hsp70 inducer enhanced suppressed nuclear accumulation of mutant AR, resulting in mitigation of neurotoxicity exerted by expanded polyglutamine. Oral administration of GGA also alleviated neuronal dysfunction in SBMA mice.Oral administration of sodium butyrate, a histone deacetylase inhibitor, upregulated histone acetylation and ameliorated phenotypes of SBMA mice, although therapeutic window of sodium butyrate was narrow.Our results suggest that inhibition of nuclear AR accumulation, enhancement of AR degradation, and restoration of transcription are the targets in pathogenesis-based therapeutic strategies for SBMA. (266 words)