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PNAS 97 (2): 657-661

Copyright © 2000 by the National Academy of Sciences.


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

Marc I. Diamond*,{dagger}, Melissa R. Robinson{ddagger}, and Keith R. Yamamoto{dagger},§

Departments of *Neurology and {dagger}Cellular and Molecular Pharmacology, and {ddagger}School of Medicine, University of California, San Francisco, CA 94143

Contributed by Keith R. Yamamoto

Accepted for publication November 23, 1999.

Abstract: Spinobulbar muscular atrophy and Huntington's disease are caused by polyglutamine expansion in the androgen receptor and huntingtin, respectively, and their pathogenesis has been associated with abnormal nuclear localization and aggregation of truncated 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 derived 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 terminus of GR abolished this activity. Surprisingly, deletion of a transcriptional regulatory domain within the GR N terminus markedly increased aggregation and nuclear localization of the expanded polyglutamine proteins. Thus, aggregation and nuclear localization of expanded polyglutamine proteins are regulated cellular processes that can be modulated by a well-characterized transcriptional regulator, the GR. Our findings suggest approaches to study the molecular pathogenesis and selective neuronal degeneration of polyglutamine expansion diseases.

§ To whom reprint requests should be addressed at: Box 0450, University of California, San Francisco, CA 94143-0450. E-mail: yamamoto{at}

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