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Treatment of polyglutamine disease using small molecular compound

小分子化合物治疗多聚谷氨酰胺病

基本信息

批准号：
17209032
负责人：
SOBUE Gen
金额：
$ 32.28万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

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)

脊髓和球部萎缩(SBMA)是一种由编码雄激素受体(AR)的基因突变引起的运动神经元疾病。我们已经阐明了这种疾病的发病机制是雄激素依赖的，雄激素剥夺治疗抑制了SBMA的神经退行性变。这些结果现在已经在临床试验中得到了验证。此外，我们还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聚谷氨酰胺疾病的发病机制有关。在细胞模型中，17-烯丙氨基格尔达那霉素以剂量依赖的方式促进突变AR蛋白的降解。该化合物还改善了SBMA小鼠模型的肌肉萎缩和运动无力。另一方面，热休克蛋白诱导剂香叶基香叶基丙酮可上调HSP70在脊髓中的表达，并改善同一模型小鼠的运动功能障碍。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，寻找可作为替代终点的生物标志物是重要的。突变AR在阴囊皮肤的蓄积程度反映了脊髓的蓄积程度，并与SBMA患者的临床严重程度相关。这些发现表明，突变AR在阴囊皮肤中的聚集是反映SBMA发病机制的一个有前景的生物标志物。我们还证明了突变AR的核聚集导致dynactin1转录失调，导致SBMA远端轴突中神经丝的异常沉积。因此，轴突运输障碍是SBMA等运动神经元病的重要治疗靶点。(245字)