These authors contributed equally to this work.
Binding of the repressor complex REST-mSIN3b by small molecules restores neuronal gene transcription in Huntington's disease models
Article first published online: 19 JUL 2013
© 2013 International Society for Neurochemistry
Journal of Neurochemistry
Volume 127, Issue 1, pages 22–35, October 2013
How to Cite
J. Neurochem.(2013) 127, 22–35
- Issue published online: 24 SEP 2013
- Article first published online: 19 JUL 2013
- Accepted manuscript online: 26 JUN 2013 02:20AM EST
- Manuscript Accepted: 17 JUN 2013
- Manuscript Revised: 10 JUN 2013
- Manuscript Received: 26 APR 2013
- STEM-HD. Grant Number: LSHB-CT-2006-037349
- Huntington's Disease Society of America Coalition for the Cure
- BDNF ;
- Huntington's disease (HD);
- protein–protein interaction;
- virtual drug screening
Transcriptional dysregulation is a hallmark of Huntington's disease (HD) and one cause of this dysregulation is enhanced activity of the REST-mSIN3a-mSIN3b-CoREST-HDAC repressor complex, which silences transcription through REST binding to the RE1/NRSE silencer. Normally, huntingtin (HTT) prevents this binding, allowing expressing of REST target genes. Here, we aimed to identify HTT mimetics that disrupt REST complex formation in HD. From a structure-based virtual screening of 7 million molecules, we selected 94 compounds predicted to interfere with REST complex formation by targeting the PAH1 domain of mSIN3b. Primary screening using DiaNRSELuc8 cells revealed two classes of compounds causing a greater than two-fold increase in luciferase. In particular, quinolone-like compound 91 (C91) at a non-toxic nanomolar concentration reduced mSIN3b nuclear entry and occupancy at the RE1/NRSE within the Bdnf locus, and restored brain-derived neurotrophic factor (BDNF) protein levels in HD cells. The mRNA levels of other RE1/NRSE-regulated genes were similarly increased while non-REST-regulated genes were unaffected. C91 stimulated REST-regulated gene expression in HTT-knockdown Zebrafish and increased BDNF mRNA in the presence of mutant HTT. Thus, a combination of virtual screening and biological approaches can lead to compounds reducing REST complex formation, which may be useful in HD and in other pathological conditions.
Dysregulation of REST and its target genes have been implicated in Huntington's disease. We have coupled structured-based virtual screening approaches to biological assays and selected molecules that interfere with the repressor complex REST-mSIN3b. In particular, at the non-toxic dose, compound C91 is able to increase neuronal gene transcription and to reverse low Bdnf mRNA levels in HD models.