Journal Article

A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor

Federica Piccioni, Benjamin R. Roman, Kenneth H. Fischbeck and J. Paul Taylor

in Human Molecular Genetics

Volume 13, issue 4, pages 437-446
Published in print February 2004 | ISSN: 0964-6906
Published online January 2004 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddh045
A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor

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Spinobulbar muscular atrophy is a neurodegenerative disorder caused by expansion of a CAG triplet repeat sequence encoding a polyglutamine tract in the androgen receptor. It has been shown that the mutant protein is toxic in cell culture and triggers an apoptotic cascade resulting in activation of caspase-3. We developed an assay of caspase-3 activation in cells expressing the mutant androgen receptor. This assay was used to screen 1040 drugs, most of which are approved for clinical use. Drugs that inhibit polyglutamine-dependent activation of caspase-3 were subjected to follow-up screens to identify compounds that reproducibly prevent polyglutamine-induced cytotoxicity. Four drugs satisfied these criteria. Three of these (digitoxin, nerifolin and peruvoside) are structurally and functionally related compounds of the cardiac glycoside class and known inhibitors of Na+K+-ATPase. The fourth compound, suloctidil, is a calcium channel blocker.

Journal Article.  5818 words.  Illustrated.

Subjects: Genetics and Genomics

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