title: Connectivity mapping uncovers small molecules that modulate neurodegeneration in Huntington's disease models.
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.
  
  
  CONCLUSIONS
  Single-endpoint chemical screens have low therapeutic discovery hit-rates. In the context of HD, we guided a chemical screen using gene expression data. The resulting chemicals were highly enriched for suppressors of mutant HTT fragment toxicity. This study provides a proof of concept for wider usage in all chemical screening.
authors.affiliation: Department of Genetics, University of Leicester, Leicester, LE1 7RH, UK.|MRC Toxicology Unit, University of Leicester, Leicester, LE1 7HB, UK.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Smalley
authors.affiliation: Department of Genetics, University of Leicester, Leicester, LE1 7RH, UK.
authors.forename: Carlo
authors.initials: C
authors.lastname: Breda
authors.affiliation: Department of Genetics, University of Leicester, Leicester, LE1 7RH, UK.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Mason
authors.affiliation: Department of Genetics, University of Leicester, Leicester, LE1 7RH, UK.
authors.forename: Gurdeep
authors.initials: G
authors.lastname: Kooner
authors.affiliation: Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, LE1 7RH, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.affiliation: MRC Toxicology Unit, University of Leicester, Leicester, LE1 7HB, UK.|Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Harwell Campus, Oxfordshire, OX11 0RQ, UK.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Gant
authors.affiliation: Department of Genetics, University of Leicester, Leicester, LE1 7RH, UK. fg36@le.ac.uk.
authors.forename: Flaviano
authors.initials: F
authors.lastname: Giorgini
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D016000:Cluster Analysis; D063132:Connectome; D003676:Deferoxamine / Q000494:pharmacology; D004195:Disease Models, Animal; D004330:Drosophila; D055808:Drug Discovery; D005786:Gene Expression Regulation; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002479:Inclusion Bodies / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D010641:Phenotype
chemical_list: D009419:Nerve Tissue Proteins; D009840:Oligomycins; D020169:Caspases; D003676:Deferoxamine
keywords: Chemical screening; Connectivity Map; Huntingtin; Huntington’s; Therapeutic detection; cMap