Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy.
Synergic prodegradative activity of Bicalutamide and trehalose on the mutant androgen receptor responsible for spinal and bulbar muscular atrophy.
复制标题
dicalutamide和Tehalose对突变体雄激素受体的协同产生活性，负责脊柱和鳞茎肌肉萎缩。
DOI：
10.1093/hmg/ddu419
复制
发表时间：
2015-01-01
影响因子：
3.5
通讯作者：
Poletti A
中科院分区：
文献类型：
--
作者：
Giorgetti E;Rusmini P;Crippa V;Cristofani R;Boncoraglio A;Cicardi ME;Galbiati M;Poletti A
脊髓延髓肌萎缩症（SBMA）是一种X连锁运动神经元疾病，由于雄激素受体（AR）基因中的CAG三重重复扩增，其被翻译成AR蛋白（ARpolyQ）中的延长的聚谷氨酰胺（polyQ）束。ARpolyQ毒性由AR配体睾酮（或二氢睾酮）激活，并且polyQ触发ARpolyQ在脊髓运动神经元和肌肉细胞中的错误折叠和聚集。在运动神经元中，睾酮通过诱导AR核转位触发核毒性。因此，（i）ARpolyQ核定位的预防，与（ii）增加的ARpolyQ细胞质清除相结合，应当降低其有害活性。使用抗雄激素比卡鲁胺（Casodex®），减缓AR激活和核转位，和二糖海藻糖，自噬激活剂，我们发现，在运动神经元中，这两种化合物一起减少ARpolyQ不溶性形式的效率高于单一处理。ARpolyQ清除率是由海藻糖诱导的自噬结合ARpolyQ与比卡鲁胺结合的较长细胞质保留介导的。这使得自噬系统在错误折叠的物质迁移到细胞核之前能够增加对它们的识别。有趣的是，海藻糖和比卡鲁胺的组合使用也可有效去除具有非常长的polyQ（Q112）道的不溶性AR物质，其通常聚集到细胞核中。总的来说，这些数据表明，比卡鲁胺和海藻糖的联合使用是促进ARpolyQ清除的一种新方法，必须在SBMA的其他靶细胞类型（即肌细胞）和SBMA动物模型中进行体内试验。
Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease due to a CAG triplet-repeat expansion in the androgen receptor (AR) gene, which is translated into an elongated polyglutamine (polyQ) tract in AR protein (ARpolyQ). ARpolyQ toxicity is activated by the AR ligand testosterone (or dihydrotestosterone), and the polyQ triggers ARpolyQ misfolding and aggregation in spinal cord motoneurons and muscle cells. In motoneurons, testosterone triggers nuclear toxicity by inducing AR nuclear translocation. Thus, (i) prevention of ARpolyQ nuclear localization, combined with (ii) an increased ARpolyQ cytoplasmic clearance, should reduce its detrimental activity. Using the antiandrogen Bicalutamide (Casodex®), which slows down AR activation and nuclear translocation, and the disaccharide trehalose, an autophagy activator, we found that, in motoneurons, the two compounds together reduced ARpolyQ insoluble forms with higher efficiency than that obtained with single treatments. The ARpolyQ clearance was mediated by trehalose-induced autophagy combined with the longer cytoplasmic retention of ARpolyQ bound to Bicalutamide. This allows an increased recognition of misfolded species by the autophagic system prior to their migration into the nucleus. Interestingly, the combinatory use of trehalose and Bicalutamide was also efficient in the removal of insoluble species of AR with a very long polyQ (Q112) tract, which typically aggregates into the cell nuclei. Collectively, these data suggest that the combinatory use of Bicalutamide and trehalose is a novel approach to facilitate ARpolyQ clearance that has to be tested in other cell types target of SBMA (i.e. muscle cells) and in vivo in animal models of SBMA.
登录
查看更多内容
影响因子：
14.5
作者：
Adachi, H;Katsuno, M;Sobue, G
通讯作者：
Sobue, G
影响因子：
16.2
作者：
Katsuno, M;Adachi, H;Sobue, G
通讯作者：
Sobue, G
影响因子：
64.8
作者：
LASPADA, AR;WILSON, EM;FISCHBECK, KH
通讯作者：
FISCHBECK, KH
影响因子：
3.5
作者：
Lieberman, AP;Harmison, G;Fischbeck, KH
通讯作者：
Fischbeck, KH
影响因子：
4.3
作者：
Chevalier-Larsen, Erica S.;Merry, Diane E.
通讯作者：
Merry, Diane E.