Huntington disease (HD) was first described in 1872 by George Huntington and is a late-onset, autosomal dominant, inherited neurodegenerative disorder. It is caused by a CAG repeat expansion mutation in exon 1 of the HTT gene resulting in an expanded polyglutamine (polyQ) tract in the huntingtin protein. The expanded polyQ tract of mutated HTT results in toxic gains-of-function of the protein, the generation of small fragments of HTT, the appearance of aggregates and disruption of various cellular processes. Eventually these events lead to cell death, most prominent in the neurons of the striatum. We have previously identified a novel mechanism that leads to the generation of the most toxic fragment of HTT: exon 1 HTT. This fragment consists only of exon 1 of the HTT gene including the polyQ tract. The generation of this fragment is based on a block in the correct splicing reaction of exon 1 HTT to exon 2 HTT resulting in the generation of a novel small RNA HTT1a. This RNA-based pathogenic process occurs in all models of HD, and most importantly also in human HTT mutation carriers.

We use a combination of molecular biology and systems biology approaches to unravel mechanisms driving HD pathogenesis. We design, establish and analyse new models for certain aspects of pathogenetic mechanisms in HD. We generate and analyse 'big data' in the context of HD. These datasets come from various biological sources and we use state-of-the-art technologies and bioinformatics to evaluate and integrate the 'omics datasets. We are interested in the contribution of RNA-based mechanisms to cell (-type specific) toxicity in HD. In particular we try to unravel mechanisms that contribute to the incomplete splicing of the HTT mRNA. We analyse how information regulating RNA biology is exchanged between cells.