Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor

摘要

Spinobulbar muscular atrophy and Huntington's disease are caused by polyglutamine expansion in the androgen receptor and huntingtin, respectively. and their pathogenesis has been associ- ated with abnormal nuclear localization and aggregation of trun- cated forms of these proteins. Here we show, in diverse cell types, that glucocorticoids can up- or down-modulate aggregation and nuclear localization of expanded polyglutamine polypeptides de- rived from the androgen receptor and huntingtin through specific regulation of gene expression. Wild-type glucocorticoid receptor (GR), as well as C-terminal deletion derivatives. suppressed the aggregation and nuclear localization of these polypeptides, whereas mutations within the DNA binding domain and N termi- nus of GR'abolished this activity. Surprisingly, deletion of a tran- scriptional regulatory domain within the GR N terminus markedly increased aggregation and nuclear localization of the expanded polyglutamine proteins. Thus, aggregation and nuclear localiza- tion of expanded polyglutamine proteins are regulated cellular processes that can be modulated by a well-characterized transcrip- tional regulator, the GR. Our findings suggest approaches to study the molecular pathogenesis and selective neuronal degeneration of polyglutamine expansion diseases.