Genistein, a natural product derived from soybeans, ameliorates polyglutamine‐mediated motor neuron disease
Genistein, a natural product derived from soybeans, ameliorates polyglutamine‐mediated motor neuron disease
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DOI：
10.1111/jnc.12172
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发表时间：
2013-07
影响因子：
4.7
通讯作者：
Qiang Qiang-Qiang;H. Adachi;Zhe Huang;Yue‐Mei Jiang;M. Katsuno;Makoto Minamiyama;H. Doi;Shin-jiro Matsumoto-Shin-j
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文献类型：
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作者：
Qiang Qiang-Qiang;H. Adachi;Zhe Huang;Yue‐Mei Jiang;M. Katsuno;Makoto Minamiyama;H. Doi;Shin-jiro Matsumoto-Shin-j
脊髓和球部肌萎缩症(SBMA)是一种遗传性运动神经元疾病，由雄激素受体(AR)基因内的多聚谷氨酰胺(PolyQ)区扩张引起。SBMA的病理特征是脊髓和脑干运动神经元丢失，残留运动神经元和某些内脏器官弥漫性核积聚和突变型AR核包涵体。AR相关辅助调节因子70(ARA70)是第一个被发现的AR辅助调节因子，已被证明与AR相互作用并增加其蛋白质稳定性。在这里，我们报告了大豆中发现的一种异黄酮染料木素，在神经细胞和SBMA转基因小鼠模型中，它扰乱了AR和ARA70之间的相互作用，并促进了突变AR的降解。我们还证明，膳食金雀异黄素改善了SBMA转基因小鼠的行为异常，改善了脊髓和肌肉病理，并减少了单体AR和高分子量突变AR蛋白聚合体的数量。因此，染料木素治疗可能是一种通过干扰AR和ARA70之间的相互作用来缓解SBMA症状的潜在治疗方法。
Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor (AR) gene. The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem, and diffuse nuclear accumulation and nuclear inclusions of mutant AR in residual motor neurons and certain visceral organs. AR‐associated coregulator 70 (ARA70) was the first coregulator of AR to be identified, and it has been shown to interact with AR and increase its protein stability. Here, we report that genistein, an isoflavone found in soy, disrupts the interaction between AR and ARA70 and promotes the degradation of mutant AR in neuronal cells and transgenic mouse models of SBMA. We also demonstrate that dietary genistein ameliorates behavioral abnormalities, improves spinal cord and muscle pathology, and decreases the amounts of monomeric AR and high‐molecular‐weight mutant AR protein aggregates in SBMA transgenic mice. Thus, genistein treatment may be a potential therapeutic approach for alleviating the symptoms of SBMA by disrupting the interactions between AR and ARA70.