Format

Send to

Choose Destination
Drug Discov Today. 2014 Jul;19(7):956-62. doi: 10.1016/j.drudis.2014.03.016. Epub 2014 Mar 21.

Transcriptional dysregulation in Huntington's disease: a failure of adaptive transcriptional homeostasis.

Author information

1
Burke Medical Research Institute, White Plains, NY 10065, USA; Brain and Mind Research Institute, Weill Medical College, Cornell University, White Plains, NY 10605, USA. Electronic address: amk3001@med.cornell.edu.
2
Burke Medical Research Institute, White Plains, NY 10065, USA.
3
Burke Medical Research Institute, White Plains, NY 10065, USA; Brain and Mind Research Institute, Weill Medical College, Cornell University, White Plains, NY 10605, USA; Department of Neurology, Weill Medical College, Cornell University, White Plains, NY 10605, USA. Electronic address: rratan@burke.org.

Abstract

Huntington's disease (HD) is a signature polyglutamine disorder. An enduring theory of HD pathogenesis has involved dysregulation of transcription. Indeed, transcriptional regulatory proteins can be modulated to overcome cardinal features of HD-modeled mice, and efforts to move these into human studies are ongoing. Here, we discuss a unifying hypothesis emerging from these studies, which is that HD represents the pathological disruption of evolutionarily conserved adaptive gene programs to counteract oxidative stress, mitochondrial dysfunction and accumulation of misfolded proteins. Transcriptional dyshomeostasis of adaptive genes is further exacerbated by repression of genes involved in normal synaptic activity or growth factor signaling.

PMID:
24662036
PMCID:
PMC4082751
DOI:
10.1016/j.drudis.2014.03.016
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center