期刊
HUMAN MOLECULAR GENETICS
卷 13, 期 4, 页码 437-446出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddh045
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资金
- NINDS NIH HHS [K22-NS44125-01] Funding Source: Medline
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.
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