High-Content Chemical and RNAi Screens for Suppressors of Neurotoxicity in a Huntington's Disease Model
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Schulte-2011-High-Content Chemica.pdf
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1.68 MB
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Author(s)
Wu, Chaohong
Hong, Pengyu
Schulte, Joost
Sepp, Katharine J.
Littleton, J. Troy
Date Issued
August 2011
Journal
PLoS ONE
Publisher
Public Library of Science
Citation
Schulte, Joost et al. “High-Content Chemical and RNAi Screens for Suppressors of Neurotoxicity in a Huntington’s Disease Model.” Ed. Mark R. Cookson. PLoS ONE 6.8 (2011): e23841. Web. 15 Feb. 2012.
Version
Final published version
Abstract
To identify Huntington's Disease therapeutics, we conducted high-content small molecule and RNAi suppressor screens using a Drosophila primary neural culture Huntingtin model. Drosophila primary neurons offer a sensitive readout for neurotoxicty, as their neurites develop dysmorphic features in the presence of mutant polyglutamine-expanded Huntingtin compared to nonpathogenic Huntingtin. By tracking the subcellular distribution of mRFP-tagged pathogenic Huntingtin and assaying neurite branch morphology via live-imaging, we identified suppressors that could reduce Huntingtin aggregation and/or prevent the formation of dystrophic neurites. The custom algorithms we used to quantify neurite morphologies in complex cultures provide a useful tool for future high-content screening approaches focused on neurodegenerative disease models. Compounds previously found to be effective aggregation inhibitors in mammalian systems were also effective in Drosophila primary cultures, suggesting translational capacity between these models. However, we did not observe a direct correlation between the ability of a compound or gene knockdown to suppress aggregate formation and its ability to rescue dysmorphic neurites. Only a subset of aggregation inhibitors could revert dysmorphic cellular profiles. We identified lkb1, an upstream kinase in the mTOR/Insulin pathway, and four novel drugs, Camptothecin, OH-Camptothecin, 18β-Glycyrrhetinic acid, and Carbenoxolone, that were strong suppressors of mutant Huntingtin-induced neurotoxicity. Huntingtin neurotoxicity suppressors identified through our screen also restored viability in an in vivo Drosophila Huntington's Disease model, making them attractive candidates for further therapeutic evaluation.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
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DOI of Published Version
https://doi.org/10.1371/journal.pone.0023841
