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Title: Connectivity mapping uncovers small molecules that modulate neurodegeneration in Huntington's disease models
Authors: Smalley, Joshua L.
Breda, Carlo
Mason, Robert P.
Kooner, Gurdeep
Luthi-Carter, Ruth
Gant, T. W.
Giorgini, Flaviano
First Published: 2-Oct-2015
Citation: Journal of Molecular Medicine, 2016, 94 (2), pp. 235-245
Abstract: Huntington’s disease (HD) is a genetic disease caused by a CAG trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin (HTT) protein, ultimately leading to neuronal loss and consequent cognitive decline and death. As no treatments for HD currently exist, several chemical screens have been performed using cell-based models of mutant HTT toxicity. These screens measured single disease-related endpoints, such as cell death, but had low ‘hit rates’ and limited dimensionality for therapeutic detection. Here, we have employed gene expression microarray analysis of HD samples—a snapshot of the expression of 25,000 genes—to define a gene expression signature for HD from publically available data. We used this information to mine a database for chemicals positively and negatively correlated to the HD gene expression signature using the Connectivity Map, a tool for comparing large sets of gene expression patterns. Chemicals with negatively correlated expression profiles were highly enriched for protective characteristics against mutant HTT fragment toxicity in in vitro and in vivo models. This study demonstrates the potential of using gene expression to mine chemical activity, guide chemical screening, and detect potential novel therapeutic compounds.
DOI Link: 10.1007/s00109-015-1344-5
ISSN: 0946-2716
eISSN: 1432-1440
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2015. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Genetics

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