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Updated: Aug 29, 2026
Caenorhabditis elegans as a Model System for Discovering Bioactive Compounds Against Polyglutamine-Mediated Neurotoxicity
Published on: September 21, 2021
A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor
Federica Piccioni1, Benjamin R Roman, Kenneth H Fischbeck
1Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MS 20892-1250, USA.
Abstract:
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.
Insights
This study screened 1040 drugs to find treatments for spinobulbar muscular atrophy. Four drugs, including cardiac glycosides and a calcium channel blocker, were found to prevent cell death caused by the disease.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disorder linked to expanded CAG repeats in the androgen receptor gene.
- Mutant androgen receptor protein is toxic, initiating apoptosis via caspase-3 activation.
Purpose of the Study:
- To develop an assay for caspase-3 activation in SBMA cells.
- To screen drugs for their ability to inhibit polyglutamine-induced cytotoxicity and caspase-3 activation.
Main Methods:
- Developed a caspase-3 activation assay for SBMA.
- Screened 1040 drugs, focusing on FDA-approved compounds.
- Conducted follow-up screens to confirm efficacy in preventing cytotoxicity.
Main Results:
- Identified four drugs that inhibit polyglutamine-dependent caspase-3 activation and prevent SBMA cell death.
- Three identified drugs (digitoxin, nerifolin, peruvoside) are cardiac glycosides inhibiting Na(+)K(+)-ATPase.
- The fourth drug, suloctidil, is a calcium channel blocker.
Conclusions:
- Cardiac glycosides and suloctidil show potential for treating SBMA.
- The developed assay is effective for screening SBMA therapeutics.
