Editors' ChoiceNeurobiology

Glucocorticoid-Controlled Localization of Disease Proteins

Science's STKE  25 Jan 2000:
Vol. 2000, Issue 16, pp. tw7
DOI: 10.1126/stke.2000.16.tw7

Huntington's disease and spinobulbar muscular atrophy belong to a group of neurological disorders caused by polyglutamine expansion within the gene of a specific protein, which leads to aggregation of the mutant protein, nuclear localization, and cytotoxicity. Polyglutamine expansion occurs when additional CAG codons are inserted into a specific gene leading to the enlargement of a polyglutamine tract in the target protein. Polyglutamine expansion of the androgen receptor and the huntingtin protein are responsible for spinobulbar muscular atrophy and Huntington's disease, respectively. Diamond et al. found that the aggregation and nuclear localization of a polyglutamine-expanded huntingtin protein and a truncated, polyglutamine-expanded androgen receptor were regulated through transcriptional activity of the glucocorticoid receptor. Stimulation of the glucocorticoid receptor led to a decrease in aggregation and nuclear accumulation, which was dependent on the activity of the transcriptional regulatory domain AF-1 in the NH2-terminus of the glucocorticoid receptor. In cells expressing glucocorticoid receptors with mutations or deletions in the AF-1 domain, exposure to glucocorticoids actually increased the accumulation of nuclear aggregates and cytotoxicity of the androgen receptor fragment and the huntingtin protein. Their data suggest that the aggregation and nuclear localization of proteins that contain expanded tracts of polyglutamines is a regulated process controlled by glucocorticoids.

Diamond, M.I., Robinson, M.R., and Yamamoto, K.R. (2000) Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor. Proc. Natl. Acad. Sci. U.S.A. 97: 657-661. [Abstract] [Full Text]