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

脊髓和球性肌萎缩症（Spinal and bulbar muscular atrophy， SBMA）是一种影响成年男性的遗传性运动神经元疾病，由雄激素受体（雄激素受体）基因CAG三核苷酸重复扩增引起。SBMA患者脊髓的组织病理学分析表明，突变AR在脊髓运动和感觉神经元的弥漫性核积累程度与CAG重复长度密切相关。携带含有97个cag的人AR全长基因的SBMA转基因小鼠模型在表型上存在显著的性别差异，且雄性比雌性更先进。手术阉割或LHRH类似物治疗的睾酮剥夺抑制突变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。目前正在对SBMA患者进行LHRH类似物的临床试验。SBMA转基因小鼠与过表达人Hsp70的小鼠杂交，抑制突变AR的核积累，显著改善运动功能。Hsp70不仅抑制突变体AR的聚集，而且促进了该蛋白的降解。在SBMA的细胞培养模型中，香叶酮、香叶酮、Hsp70诱导剂增强了抑制突变AR的核积累，从而减轻了膨胀型聚谷氨酰胺施加的神经毒性。口服GGA还可减轻SBMA小鼠的神经功能障碍。口服丁酸钠（一种组蛋白去乙酰化酶抑制剂）可以上调组蛋白乙酰化，改善SBMA小鼠的表型，尽管丁酸钠的治疗窗口很窄。我们的研究结果表明，抑制核AR积累、增强AR降解和恢复转录是基于发病机制的SBMA治疗策略的目标。(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)