PDF(Pubmed)
Abstract：
Nine polyglutamine (polyQ) proteins have already been identified that are considered to be associated with the pathologies of neurodegenerative disorders called polyQ diseases, but whether these polyQ proteins mutually interact and synergize in proteinopathies remains to be elucidated. In this study, 4 polyQ-containing proteins, androgen receptor (AR), ataxin-7 (Atx7), huntingtin (Htt) and ataxin-3 (Atx3), are used as model molecules to investigate their heterologous coaggregation and consequent impact on cellular proteostasis. Our data indicate that the N-terminal fragment of polyQ-expanded (PQE) Atx7 or Htt can coaggregate with and sequester AR and Atx3 into insoluble aggregates or inclusions through their respective polyQ tracts. In vitro coprecipitation and NMR titration experiments suggest that this specific coaggregation depends on polyQ lengths and is probably mediated by polyQ-tract interactions. Luciferase reporter assay shows that these coaggregation and sequestration effects can deplete the cellular availability of AR and consequently impair its transactivation function. This study provides valid evidence supporting the viewpoint that coaggregation of polyQ proteins is mediated by polyQ-tract interactions and benefits our understanding of the molecular mechanism underlying the accumulation of different polyQ proteins in inclusions and their copathological causes of polyQ diseases.
摘要：
已经鉴定出九种聚谷氨酰胺（polyQ）蛋白，它们被认为与称为polyQ疾病的神经退行性疾病的病理有关。但是这些polyQ蛋白在蛋白质疾病中是否相互作用和协同作用仍有待阐明。在这项研究中,4种含有polyQ的蛋白质，雄激素受体(AR),ataxin-7(Atx7),亨廷顿蛋白（Htt）和ataxin-3（Atx3），用作模型分子，以研究它们的异源共聚集和对细胞蛋白稳定的影响。我们的数据表明，polyQ扩展（PQE）Atx7或Htt的N端片段可以通过其各自的polyQ片段与AR和Atx3共聚集并隔离为不溶性聚集体或内含物。体外共沉淀和NMR滴定实验表明，这种特定的共聚集取决于polyQ长度，并且可能是由polyQ束相互作用介导的。荧光素酶报告基因测定表明,这些共聚集和螯合作用可以耗尽AR的细胞可用性,并因此损害其反式激活功能。这项研究提供了有效的证据支持以下观点：polyQ蛋白的共聚集是由polyQ-trans相互作用介导的，并且有利于我们对不同polyQ蛋白在内含物中积累的分子机制及其polyQ疾病的共病原因的理解。
