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Connectivity mapping uncovers small molecules that modulate neurodegeneration in Huntington's disease models

journal contribution
posted on 2015-10-08, 10:09 authored by Joshua L. Smalley, Carlo Breda, Robert P. Mason, Gurdeep Kooner, Ruth Luthi-Carter, T. W. Gant, Flaviano Giorgini
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.

History

Citation

Journal of Molecular Medicine, 2016, 94 (2), pp. 235-245

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/MBSP Non-Medical Departments/Department of Genetics

Version

  • VoR (Version of Record)

Published in

Journal of Molecular Medicine

issn

0946-2716

eissn

1432-1440

Acceptance date

2015-09-09

Copyright date

2015

Available date

2015-10-08

Publisher version

http://link.springer.com/article/10.1007/s00109-015-1344-5

Language

en

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