Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy
Cytoplasmic retention of polyglutamine-expanded androgen receptor ameliorates disease via autophagy in a mouse model of spinal and bulbar muscular atrophy
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DOI：
10.1093/hmg/ddp115
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发表时间：
2009-06-01
影响因子：
3.5
通讯作者：
Merry, Diane E.
中科院分区：
文献类型：
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作者：
Montie, Heather L.;Cho, Maria S.;Merry, Diane E.
在许多聚谷氨酰胺疾病中，细胞核是蛋白质聚集的主要部位，这表明在发病机制中发挥了中心作用。在SBMA中，核进一步受到雄激素对疾病的关键作用的影响，雄激素促进突变的雄激素受体(AR)的核转位。为了阐明核在SBMA中的重要性，我们从基因上操纵了聚谷氨酰胺扩展的AR的核定位信号。与SBMA小鼠相比，表达该突变AR的转基因小鼠表现出低效率的核转位和显著的运动功能改善。虽然我们发现SBMA需要多谷氨酰胺扩展的AR的核定位，但我们也发现，使用SBMA的细胞模型，它不足以满足聚集和毒性，并且需要雄激素来实现这些疾病特征。通过对培养的运动神经元的研究，我们进一步发现，自噬途径能够降解细胞质，保留扩张的AR，并代表一种内源性神经保护机制。此外，自噬的药理诱导将运动神经元从即使是居住在核的突变AR的毒性效应中解救出来，表明自噬在这种以核为中心的疾病中具有治疗作用。因此，我们的研究证实，聚谷氨酰胺扩展的AR必须在其配体存在的情况下驻留在细胞核内，才能引起SBMA。他们还强调了在SBMA神经毒性中要求核定位的一个机制基础，即缺乏通过自噬蛋白降解途径去除突变的AR。
The nucleus is the primary site of protein aggregation in many polyglutamine diseases, suggesting a central role in pathogenesis. In SBMA, the nucleus is further implicated by the critical role for disease of androgens, which promote the nuclear translocation of the mutant androgen receptor (AR). To clarify the importance of the nucleus in SBMA, we genetically manipulated the nuclear localization signal of the polyglutamine-expanded AR. Transgenic mice expressing this mutant AR displayed inefficient nuclear translocation and substantially improved motor function compared with SBMA mice. While we found that nuclear localization of polyglutamine-expanded AR is required for SBMA, we also discovered, using cell models of SBMA, that it is insufficient for both aggregation and toxicity and requires androgens for these disease features. Through our studies of cultured motor neurons, we further found that the autophagic pathway was able to degrade cytoplasmically retained expanded AR and represents an endogenous neuroprotective mechanism. Moreover, pharmacologic induction of autophagy rescued motor neurons from the toxic effects of even nuclear-residing mutant AR, suggesting a therapeutic role for autophagy in this nucleus-centric disease. Thus, our studies firmly establish that polyglutamine-expanded AR must reside within nuclei in the presence of its ligand to cause SBMA. They also highlight a mechanistic basis for the requirement for nuclear localization in SBMA neurotoxicity, namely the lack of mutant AR removal by the autophagic protein degradation pathway.