Role of USP7 in pathogenicity of spinal and bulbar muscular atrophy

多聚谷氨酰胺（polyQ）疾病是一个缓慢进展的神经退行性疾病家族， 通过在不同和不相关基因的编码区内的CAG三联体重复扩增。脊柱 球肌萎缩症（SBMA）就是一种以大脑丧失为特征的疾病 干和脊髓运动神经元，以及相关的神经支配肌肉。这种毒性对 神经肌肉系统是由CAG重复编码的polyQ片段在神经肌肉系统内的扩展引起的。 雄激素受体蛋白，一种由其同源配体激活的转录因子， 睾酮和双氢睾酮。尽管介导这些分子的活动 扩展的polyQ依赖性毒性在很大程度上仍然不清楚，这种长的polyQ束被认为 通过蛋白质-蛋白质相互作用失调引起细胞功能障碍并最终导致细胞死亡 维持正常细胞功能因此，为了理解这种失调，我们必须 采用定量蛋白质组学方法鉴定AR蛋白相互作用的变化 PolyQ扩展引起的网络。在五个独立的实验中， 是泛素特异性蛋白酶USP 7，我们已经验证了它是一种优先与 polyQ扩增的AR。我们还观察到USP 7与SBMA转基因小鼠中polyQ扩增的AR相互作用， 小鼠此外，虽然USP 7的部分敲低减少了polyQ扩增的AR聚集， 细胞毒性，野生型的过表达，但不是催化失活，USP 7导致 polyQ扩增的AR聚集以及细胞毒性的显著增加。这些发现支持 USP 7的去泛素化酶活性在polyQ扩增的AR毒性中起作用的想法， 抑制USP 7活性可能是治疗SBMA的可行治疗策略。

Polyglutamine (polyQ) diseases are a family of slow-progressing neurodegenerative disorders caused by CAG triplet repeat expansions within the coding regions of distinct and unrelated genes. Spinal and bulbar muscular atrophy (SBMA) is one such disease that is characterized by a loss of brain stem and spinal cord motor neurons, and of the associated innervated muscles. This toxicity to the neuromuscular system is caused by the expansion of a CAG repeat-encoded polyQ segment within the androgen receptor protein, a transcription factor that is activated by its cognate ligands, testosterone and dihydrotestosterone. Although the molecular events that mediate expanded-polyQ-dependent toxicity remain largely obscure, such long polyQ tracts are thought to cause cellular dysfunction and ultimately cell death by dysregulating protein-protein interactions that sustain normal cellular function. Therefore, to understand this dysregulation, we have employed a quantitative proteomics approach to identify changes in the AR protein interaction network caused by polyQ expansion. In five independent experiments, one of the top hits identified was the ubiquitin-specific protease USP7, which we have validated as a preferential interactor with polyQ-expanded AR. We also observed that USP7 interacts with polyQ- expanded AR in SBMA transgenic mice. Moreover, while partial knockdown of USP7 reduced polyQ-expanded AR aggregation and cytotoxicity, overexpression of wild-type, but not catalytically inactive, USP7 resulted in a dramatic increase in polyQ-expanded AR aggregation as well as cytotoxicity. These findings support the idea that the deubiquitinase activity of USP7 plays a role in polyQ-expanded AR toxicity and that inhibiting USP7 activity may be a viable therapeutic strategy for the treatment of SBMA.