Cell Signaling and Neurodegeneration

描述（由申请人提供）：脊髓小脑性共济失调1型（SCA1）是一种常染色体显性神经退行性疾病，由SCA1编码蛋白ataxin-1中谷氨酰胺重复扩增引起。先前的研究表明突变体ataxin-1的亚细胞沉积和定位在SCA1的发病机制中起着关键作用。糖原合成酶激酶3 （GSK3）在许多细胞信号通路中起着关键作用，其中许多与神经变性有关。我们的研究结果表明，ataxin-1的776和780丝氨酸可能通过GSK3b的磷酸化作用，在该蛋白的亚细胞定位中发挥作用。因此，以下研究的目的是确定通过这些ataxin-1丝线作用的细胞信号通路是否具有生物学相关性。GSK3b最近成为药物发现的关键靶点。如果证实SCA1发病机制与GSK3b活性水平升高有关，那么GSK3b抑制剂可能在SCA1中具有治疗作用。

DESCRIPTION (provided by applicant): Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCA1-encoded protein ataxin-1. Previous work has shown that the subcellular deposition and localization of mutant ataxin-1 plays a critical role in the pathogenesis of SCA1. A key player in numerous cell-signaling pathways, many associated with neurodegeneration, is the enzyme glycogen synthase kinase 3 (GSK3). Our results indicate that serines 776 and 780 of ataxin-1 play a role in the subcellular localization of this protein, perhaps via their phosphorylation by GSK3b. Thus, the goal of the research described below is to determine whether cell-signaling pathways acting through these serines of ataxin-1 are biologically relevant GSK3b has recently emerged as a key target in drug discovery. If it proves to be the case that SCA1 pathogenesis is associated with increased levels of GSK3b activity, GSK3b inhibitors might have a therapeutic role in SCA1.