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.