Unveiling molecular causes of Huntington's disease
HD is a genetic disorder associated with neuronal motor dysfunction. It is caused by a trinucleotide repeat expansion in the huntingtin gene, which leads to the production of a protein that is toxic to neuronal cells. The mutant product also induces protein aggregation and an abnormal DNA damage response (DDR). Emerging evidence indicates that the trinucleotide expansion also produces small RNA molecules that are toxic to neuronal cells. However, the precise mechanism behind this RNA-mediated toxicity is not known. Given the implication of the DDR in HD pathogenesis, the EU-funded 'Small RNA toxicity and DNA damage response in Huntington's disease' (RNANEUROTOX) project worked under the hypothesis that small RNAs somehow activate the DDR, causing severe neurotoxicity. The key objective was to decipher the link between the two. Study activities were designed to provide evidence that mutant huntingtin RNA products induce a DDR in cultured cells. For this purpose, researchers obtained neuronal cells and treated them with the mutant huntingtin RNA. Microarray analysis of gene expression changes was focused on genes that are implicated in the DDR as well as on genes previously reported to be down-regulated in affected brain areas of HD patients. To further validate the association of RNA toxicity with induction of DNA damage, scientists inhibited DDR. Collectively, the results of the RNANEUROTOX research project will contribute to a better understanding of the molecular mechanisms underlying HD. The generated knowledge could be translated to other disorders and lead to novel therapeutic interventions.
Keywords
Huntington's disease, huntingtin, DNA damage response, small RNA,RNA toxicity