Monks Douglas Ashley, Johansen Jamie A, Mo Kaiguo, Rao Pengcheng, Eagleson Bryn, Yu Zhigang, Lieberman Andrew P, Breedlove S Marc, Jordan Cynthia L
Neuroscience Program and Department of Psychology, Michigan State University, East Lansing, MI 48824, USA.
Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18259-64. doi: 10.1073/pnas.0705501104. Epub 2007 Nov 2.
We created transgenic mice that overexpress WT androgen receptor (AR) exclusively in their skeletal muscle fibers. Unexpectedly, these mice display androgen-dependent muscle weakness and early death, show changes in muscle morphology and gene expression consistent with neurogenic atrophy, and exhibit a loss of motor axons. These features reproduce those seen in models of Kennedy disease, a polyglutamine expansion disorder caused by a CAG repeat expansion in the AR gene. These findings demonstrate that toxicity in skeletal muscles is sufficient to cause motoneuron disease and indicate that overexpression of the WT AR can exert toxicity comparable with the polyglutamine expanded protein. This model has two clear implications for Kennedy disease: (i) mechanisms affecting AR gene expression may cause neuromuscular symptoms similar to those of Kennedy disease and (ii) therapeutic approaches targeting skeletal muscle may provide effective treatments for this disease.
我们构建了仅在骨骼肌纤维中过表达野生型雄激素受体（AR）的转基因小鼠。出乎意料的是，这些小鼠表现出雄激素依赖性肌肉无力和早期死亡，呈现出与神经源性萎缩一致的肌肉形态和基因表达变化，并出现运动轴突丧失。这些特征重现了肯尼迪病模型中的表现，肯尼迪病是一种由AR基因中CAG重复序列扩增导致的多聚谷氨酰胺扩增疾病。这些发现表明，骨骼肌中的毒性足以导致运动神经元疾病，并表明野生型AR的过表达可产生与多聚谷氨酰胺扩增蛋白相当的毒性。该模型对肯尼迪病有两个明确的启示：（i）影响AR基因表达的机制可能导致与肯尼迪病相似的神经肌肉症状；（ii）针对骨骼肌的治疗方法可能为该疾病提供有效的治疗。
