Androgen receptor YAC Transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration
Androgen receptor YAC Transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration
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DOI：
10.1016/s0896-6273(04)00082-0
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发表时间：
2004-03-04
期刊：
影响因子：
16.2
通讯作者：
La Spada, AR
中科院分区：
文献类型：
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作者：
Sopher, BL;Thomas, PS;La Spada, AR
X连锁脊髓和延髓肌萎缩症(SBMA)是一种遗传性神经肌肉疾病，以低位运动神经元变性为特征。SBMA是由雄激素受体(AR)中的多聚谷氨酰胺重复膨胀引起的。为了确定AR多谷氨酰胺神经毒性的基础，我们将携带20或100个CAG的人AR酵母人工染色体导入小鼠胚胎干细胞。AR100转基因小鼠出现了一种起病晚、逐渐进行性的神经肌肉表型，并伴有运动神经元变性，这表明这种疾病惊人地重演了人类疾病。然后，我们验证了聚谷氨酰胺扩展的AR干扰CREB结合蛋白(CBP)介导的血管内皮生长因子(VEGF)转录的假设，并观察了AR100小鼠CBP-AR结合和VEGF减少的变化。我们发现，突变型AR诱导的运动神经元样细胞死亡可以被血管内皮生长因子所挽救。我们的结果表明，SBMA运动神经病涉及到血管内皮生长因子表达的改变，这与血管内皮生长因子作为神经营养/生存因子在运动神经元疾病中的作用是一致的。
X-linked spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder characterized by lower motor neuron degeneration. SBMA is caused by polyglutamine repeat expansions in the androgen receptor (AR). To determine the basis of AR polyglutamine neurotoxicity, we introduced human AR yeast artificial chromosomes carrying either 20 or 100 CAGs into mouse embryonic stem cells. The AR100 transgenic mice developed a late-onset, gradually progressive neuromuscular phenotype accompanied by motor neuron degeneration, indicating striking recapitulation of the human disease. We then tested the hypothesis that polyglutamine-expanded AR interferes with CREB binding protein (CBP)-mediated transcription of vascular endothelial growth factor (VEGF) and observed altered CBP-AR binding and VEGF reduction in AR100 mice. We found that mutant AR-induced death of motor neuron-like cells could be rescued by VEGF. Our results suggest that SBMA motor neuronopathy involves altered expression of VEGF, consistent with a role for VEGF as a neurotrophic/survival factor in motor neuron disease.