Kennedy disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length-dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2-4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel alpha-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line-derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy disease phenotype and suggest a role for muscle in non-cell autonomous toxicity of lower motor neurons.

译文

:肯尼迪病是一种以雄激素依赖性神经肌肉无力为特征的变性疾病,是由雄激素受体(Ar)基因中的CAG /谷氨酰胺束扩张引起的。我们开发了肯尼迪病的小鼠模型,使用基因靶向技术将小鼠雄激素受体(AR)转化为人类序列,同时引入113种谷氨酰胺。 AR113Q小鼠发展出激素和谷氨酰胺长度依赖性神经肌肉无力,其特征是肌病性和神经源性骨骼肌病理的早期发生以及脊髓神经元中神经元核内包涵体的发育较晚。 AR113Q男性意外死于2-4个月。我们表明,这种雄激素依赖性死亡反映了骨骼肌氯化物通道1(CLCN1)和骨骼肌钠通道α亚基的表达下降,导致下尿路骨骼肌的肌强直放电。 AR113Q肢体肌肉表现出相似的肌病特征,并表达编码神经营养蛋白4和神经胶质细胞源性神经营养因子的mRNA降低水平。这些数据定义了对肯尼迪病表型的重要肌病性贡献,并暗示了肌肉在下运动神经元的非细胞自主毒性中的作用。

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