Testosterone treatment fails to accelerate disease in a transgenic mouse model of spinal and bulbar muscular atrophy
Testosterone treatment fails to accelerate disease in a transgenic mouse model of spinal and bulbar muscular atrophy
复制标题
DOI：
10.1242/dmm.007849
复制
发表时间：
2012-01-01
影响因子：
4.3
通讯作者：
Merry, Diane E.
中科院分区：
文献类型：
--
作者：
Chevalier-Larsen, Erica S.;Merry, Diane E.
来自多个动物模型的证据表明，睾酮在脊髓和延髓肌萎缩症(SBMA)的症状进展中发挥关键作用，SBMA是一种导致受影响男性神经退化和肌肉萎缩的疾病。携带编码人类雄激素受体(AR)的转基因小鼠(扩展的聚谷氨酰胺束；AR112Q小鼠)复制了人类疾病的几个方面。我们用睾酮处理转基因雄性AR112Q小鼠6个月。令人惊讶的是，对AR112Q男性进行的睾酮治疗并没有加剧疾病。尽管与非转基因男性相比，转基因AR112Q男性表现出功能缺陷，但长期服用睾酮治疗对运动功能没有影响。睾酮治疗也未能影响疾病的细胞标志物，包括包涵体形成(突变AR蛋白的大核聚集体积累)和非磷酸化神经丝重链的水平。这些数据表明，SBMA的疾病机制在接近内源性激素水平的情况下饱和，患有SBMA的人如果服用或已经服用睾酮作为其假定的治疗特性，不太可能遭受不良影响。
Evidence from multiple animal models demonstrates that testosterone plays a crucial role in the progression of symptoms in spinal and bulbar muscular atrophy (SBMA), a condition that results in neurodegeneration and muscle atrophy in affected men. Mice bearing a transgene encoding a human androgen receptor (AR) that contains a stretch of 112 glutamines (expanded polyglutamine tract; AR112Q mice) reproduce several aspects of the human disease. We treated transgenic male AR112Q mice with testosterone for 6 months. Surprisingly, testosterone treatment of AR112Q males did not exacerbate the disease. Although transgenic AR112Q males exhibited functional deficits when compared with non-transgenics, long-term testosterone treatment had no effect on motor function. Testosterone treatment also failed to affect cellular markers of disease, including inclusion formation (the accumulation of large nuclear aggregates of mutant AR protein) and levels of unphosphorylated neurofilament heavy chain. These data suggest that the mechanism of disease in SBMA saturates at close to endogenous hormone levels and that individuals with SBMA who take, or have taken, testosterone for its putative therapeutic properties are unlikely to suffer adverse effects.