Treatment of polyglutamine disease using small molecular compound

脊髓和球萎缩（SBMA）是一种由雄激素受体（AR）编码基因突变引起的运动神经元疾病。我们已经描述了这种疾病的发病机制是雄激素依赖性的，雄激素剥夺治疗抑制SBMA的神经变性。这些结果现已在临床试验中得到证实。此外，我们研究了操纵热休克蛋白（HSPs）的替代治疗策略，热休克蛋白被认为与多谷氨酰胺疾病的发病机制有关。在细胞模型中，17-烯丙基氨基格尔达霉素以剂量依赖的方式促进突变AR蛋白的降解。该化合物还能改善SBMA小鼠模型的肌肉萎缩和运动无力。另一方面，在同一小鼠模型中，热休克蛋白（HSP）诱导剂香叶酮（geranylgeranyl丙酮）上调脊髓中Hsp70的表达，并改善运动功能障碍。为了对包括SBMA在内的神经退行性疾病进行有效的临床试验，确定可作为替代终点的生物标志物非常重要。突变AR在阴囊皮肤的积累程度反映了在脊髓的积累程度，并与SBMA患者的临床严重程度相关。这些发现表明，阴囊皮肤突变AR积累是反映SBMA发病机制的一个有希望的生物标志物。我们也证明了突变AR的核积累导致dynactin1的转录失调，导致SBMA远端轴突神经丝的异常沉积。因此，轴突运输的中断是运动神经元疾病（如SBMA）的重要治疗靶点。(245字)

Spinal and bulbar atrophy (SBMA) is a motor neuron disease caused by a mutation of the gene coding androgen receptor (AR). We have delineated that the pathogenesis of this disease is androgen-dependent, and that androgen deprivation therapy suppresses neurodegeneration in SBMA. These results have now been verified in clinical trials.In addition, we investigated alternative therapeutic strategies manipulating heat shock proteins (HSPs) which has been construed to be implicated in the pathogenesis of polyglutamine diseases. In a cellular model, 17-allylamino geldanamycin facilitated degradation of mutant AR protein in a dose dependent manner. This compound also improved muscular atrophy and motor weakness in a mouse model of SBMA. On the other hand, geranylgeranyl acetone, an HSP inducer, upregulated Hsp70 expression in the spinal cord, and ameliorated motor dysfunction in the same mouse model.To carry out effective clinical trials for neurodegenerative diseases including SBMA, it is of importance to identify biomarkers which can be used as a surrogate endpoint. The degree of mutant AR accumulation in the scrotal skin reflected that in the spinal cord, and is correlated with clinical severity of SBMA patients. These findings suggest that mutant AR accumulation in the scrotal skin is a promising biomarker reflecting SBMA pathogenesis.We have also demonstrated that nuclear accumulation of mutant AR causes transcriptional dysregulation of dynactin1, resulting in abnormal deposit of neurofilament in the distal axon in SBMA. Disruption of axonal transport thus is an important therapeutic target of motor neuron disease such as SBMA. (245 words)