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Compounds blocking mutant huntingtin toxicity identified using a Huntington's disease neuronal cell model
Wenfei Wang1, Wenzhen Duan, Shuichi Igarashi
1Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2109, USA.
Neurobiology of Disease
|May 24, 2005
Summary
Researchers screened 1040 compounds to find treatments for Huntington's disease (HD). Five compounds protected neuronal cells from mutant huntingtin protein toxicity in a cell model, offering potential therapeutic avenues.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Huntington's disease (HD) involves neuronal cell death, primarily due to the mutant huntingtin protein.
- A PC12 cell model expressing mutant huntingtin (N63-148Q) was previously established for studying HD.
- Lactate dehydrogenase (LDH) release is a marker for cell death.
Purpose of the Study:
- To screen compounds for their ability to protect against mutant huntingtin toxicity.
- To identify potential therapeutic agents for Huntington's disease.
Main Methods:
- Utilized an inducible PC12 cell model expressing mutant huntingtin (N63-148Q).
- Screened 1040 compounds from the NINDS Custom Collection.
- Measured LDH release as an indicator of neuronal cell death.
- Tested positive compounds at multiple concentrations.
Main Results:
- Five compounds significantly reduced mutant huntingtin-induced LDH release.
- These protective effects were independent of huntingtin expression levels or aggregate formation.
- A broad-spectrum caspase inhibitor (Z-VAD-fmk) and other candidate compounds were also tested.
Conclusions:
- The developed cell model is effective for screening potential Huntington's disease therapeutics.
- Identified five promising compounds that attenuate mutant huntingtin toxicity.
- This screening approach aids in the discovery of novel treatments for HD.