CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model
CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model
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DOI：
10.1523/jneurosci.1242-07.2007
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发表时间：
2007-05-09
影响因子：
5.3
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Adachi, Hiroaki;Waza, Masahiro;Sobue, Gen
脊髓延髓肌萎缩症（SBMA）是一种遗传性运动神经元疾病，由雄激素受体（AR）内的多聚谷氨酰胺束扩张引起。SBMA的病理特征是脊髓和脑干中的运动神经元丢失以及残余运动神经元和某些内脏器官中的突变AR的弥漫性核积聚和核包涵体。泛素-蛋白酶体和分子伴侣的许多组分也被隔离在内含物中，这表明它们可能积极参与试图降解或重折叠突变体AR。Hsc 70（热休克相关蛋白70）相互作用蛋白（CHIP）的C末端是一种U盒型E3遍在蛋白连接酶，已被证明与热休克蛋白90（Hsp 90）或Hsp 70相互作用，并使被分子伴侣捕获的未折叠蛋白遍在化并降解它们。在这里，我们证明了在神经元细胞模型中CHIP的瞬时过表达比野生型更有效地降低了单体突变体AR，这表明突变体AR对CHIP比野生型更敏感。在SBMA转基因小鼠模型中CHIP的高表达也改善了运动症状并抑制了突变体AR的神经元核积累。当CHIP在转基因SBMA小鼠中过表达时，突变体AR也优先降解野生型AR。这些发现表明CHIP过表达通过增强突变体AR降解减少核定位突变体AR来改善小鼠中的SBMA表型。因此，CHIP过表达将为SBMA提供潜在的治疗途径。
Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor (AR). The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of the mutant AR in the residual motor neurons and certain visceral organs. Many components of the ubiquitin-proteasome and molecular chaperones are also sequestered in the inclusions, suggesting that they may be actively engaged in an attempt to degrade or refold the mutant AR. C terminus of Hsc70 ( heat shock cognate protein 70)-interacting protein (CHIP), a U-box type E3 ubiquitin ligase, has been shown to interact with heat shock protein 90 (Hsp90) or Hsp70 and ubiquitylates unfolded proteins trapped by molecular chaperones and degrades them. Here, we demonstrate that transient overexpression of CHIP in a neuronal cell model reduces the monomeric mutant AR more effectively than it does the wild type, suggesting that the mutant AR is more sensitive to CHIP than is the wild type. High expression of CHIP in an SBMA transgenic mouse model also ameliorated motor symptoms and inhibited neuronal nuclear accumulation of the mutant AR. When CHIP was overexpressed in transgenic SBMA mice, mutant AR was also preferentially degraded over wild-type AR. These findings suggest that CHIP overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR via enhanced mutant AR degradation. Thus, CHIP overexpression would provide a potential therapeutic avenue for SBMA.