Role of USP7 in pathogenicity of spinal and bulbar muscular atrophy

USP7 在脊髓和延髓性肌萎缩症致病性中的作用

基本信息

批准号：
9375067
负责人：
Anna Pluciennik
金额：
$ 7.8万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9375067
关键词：
Alpha Cell Alzheimer&apos s Disease Androgen Receptor Apoptotic Brain Brain Stem CAG repeat Cell Death Cell model Cell physiology Cells Code DNA Damage Deubiquitination Disease Dose Enzymes Event Family Functional disorder Gene Silencing Genes Genetic Homeostasis Human Huntington Disease Laboratories Ligands Mediating Modification Molecular Molecular Conformation Motor Neurons Muscle Mutation Neurodegenerative Disorders Nuclear Inclusion Pathogenesis Pathogenicity Pathway interactions Pharmacology Play Post-Translational Modification Alteration Protein Conformation Protein Inhibition Proteins Proteomics Role Signal Transduction Spinal Cord Stanolone System Testing Testosterone Therapeutic Toxic effect Transcriptional Activation Transgenic Mice Trinucleotide Repeats Ubiquitination cytotoxic cytotoxicity disease phenotype experimental study in vivo inhibitor/antagonist knock-down motor disorder mouse model mutant neuromuscular system neurotoxicity novel overexpression polyglutamine protein complex protein folding protein misfolding protein protein interaction receptor response small hairpin RNA small molecule inhibitor spinal and bulbar muscular atrophy transcription factor treatment strategy ubiquitin-specific protease

项目摘要

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.

聚谷氨酰胺（Polyq）疾病是导致缓慢促进神经退行性疾病的家族通过CAG三重态在不同基因和无关基因的编码区域内重复扩展。脊和鳞茎肌肉萎缩（SBMA）就是一种疾病，其特征是脑部丧失茎和脊髓运动神经元以及相关支配的肌肉。对神经肌肉系统是由CAG重复编码PolyQ段扩展引起的雄激素受体蛋白，一种转录因子，由其同源配体激活，睾丸激素和二氢睾丸激素。虽然介导的分子事件扩展的polyQ依赖性毒性在很大程度上仍然是晦涩的，这类长polyq道被认为是引起细胞功能障碍并最终通过失调的蛋白质蛋白质相互作用而导致细胞死亡维持正常的细胞功能。因此，要了解这种失调，我们有采用定量蛋白质组学方法来识别AR蛋白相互作用的变化由PolyQ扩展引起的网络。在五个独立的实验中，最高命中之一是确定的是泛素特异性蛋白酶USP7，我们已将其验证为优先互动者与 polyq扩展的AR。我们还观察到USP7与SBMA转基因中的PolyQ-扩展AR相互作用老鼠。此外，虽然USP7的部分敲低减少了PolyQ扩展的AR聚集，并且细胞毒性，野生型的过表达，但不是催化性非活性，USP7导致了 PolyQ扩展的AR聚集以及细胞毒性的急剧增加。这些发现支持 USP7的去泛素酶活性在PolyQ扩展的AR毒性和抑制USP7活性可能是治疗SBMA的可行治疗策略。