NeuroMolecular Medicine

, Volume 11, Issue 3, pp 183–199 | Cite as

Gene Dysregulation in Huntington’s Disease: REST, MicroRNAs and Beyond

  • Rory Johnson
  • Noel J. Buckley
Original Paper


Huntington’s disease (HD) is an incurable, fatal neurodegenerative disorder that is caused by a polyglutamine expansion in the huntingtin (Htt) protein. Neuronal death in the striatum—the most obvious manifestation of the disease—is likely to result from widespread dysregulation of gene expression in various brain regions. To date, several potential mechanisms for this have been discovered, including one involving REST (RE1-Silencing Transcription Factor), a master regulator of neuronal genes. Recently, independent studies have demonstrated that post-transcriptional gene regulation by microRNAs is also disrupted in HD. Expression of key neuronal microRNAs—including mir-9/9*, mir-124 and mir-132—is repressed in the brains of human HD patients and mouse models. These changes occur downstream of REST, and are likely to result in major disruption of mRNA regulation and neuronal function. In this study we will discuss these findings and their implications for our understanding of HD. Using updated bioinformatic analysis, we predict 21 new candidate microRNAs in HD. We propose future strategies for unifying large-scale transcriptional and microRNA datasets with the aim of explaining HD aetiology. By way of example, we show how available genomic datasets can be integrated to provide independent, analytical validation for dysregulation of REST and microRNA mir-124 in HD. As a consequence, gene ontology analysis indicates that HD is characterised by a broad-based depression of neural genes in the caudate and motor cortex. Thus, we propose that a combination of REST, microRNAs and possibly other non-coding RNAs profoundly affect the neuronal transcriptome in HD.


Neurodegeneration Huntington’s disease MicroRNA Noncoding RNA REST NRSF 



Huntington’s disease




Mutant huntingtin


Brain-derived neurotrophic factor




Repressor element 1-silencing transcription factor


Repressor element 1


Neuron-restrictive silencing factor


Neuron-restrictive silencing element


Spinocerebellar ataxia


Specificity protein 1


RNA-induced silencing complex


Dentatorubral-pallidoluysian atrophy


Spinobulbar muscular atrophy


MicroRNA response element


cAMP response element binding


Methyl CpG binding protein 2


β-site of APP cleaving enzyme


Alzheimer’s disease


Noncoding RNA


Chromatin immunoprecipitation coupled to high-throughput sequencing



We wish to thank Chiara Zuccato (University of Milan), Andrew M. Thomson (Genome Institute of Singapore) and Lawrence W. Stanton (Genome Institute of Singapore) for advice, discussions and critical reading of the manuscript. RJ is a postdoctoral fellow funded by the Singapore Agency for Science, Technology and Research (A*STAR).


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Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  1. 1.Stem Cell and Developmental Biology Group, Genome Institute of SingaporeSingaporeSingapore
  2. 2.Centre for the Cellular Basis of Behaviour, Centre for Cell and Integrative Biology, King’s College London, Institute of PsychiatryLondonUK

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