DNA repair genes spur Huntington's disease development

Genes involved in DNA repair have been found to quicken the progression of Huntington's disease (HD).

Scientists at the University of California Los Angeles (UCLA) studied the role of mismatch repair genes in mice genetically modified to have HD. HD is a neurodegenerative disorder caused by a mutation in the gene Huntingtin. The mutation contains repeats of the base-pairs 'CAG', and the number of repeats differs between patients. The more this sequence is repeated, the earlier the onset of HD. Mismatch repair genes should recognise errors within DNA and correct them, however those known to be associated with HD do not work this way.

'These remarkable results demonstrate that a subset of mismatch repair genes is driving disease in vulnerable neurons because they confer the fastest rate of CAG repeat expansion in these neurons,' said Xiangdon Yang, professor in psychiatry and biobehavioural sciences at UCLA and lead author of the study. 'Our study provides mechanistic links that help to bridge modifier genes from patients, mismatch repair gene driven repeat expansion, and selective neuronal vulnerability in HD.'

According to the NHS, HD is typically diagnosed between the ages of 30 and 50, and the disease is fatal up to 20 years after onset, with symptoms worsening over time. Mismatch repair genes are known to be associated with HD, but the mechanism by which they influence the disease was not understood.

Publishing their findings in Cell, the scientists knocked out mismatch repair genes in HD mice. The mice were then tested for several characteristics of HD including impaired locomotor function. Some of the genes tested resulted in slightly different progression of the disease. The absence of four of these genes resulted in the mice having improved locomotor function. One gene, Msh3, had long-lasting effects as the mice aged.

'We were surprised to see the potent and sustained effects of targeting these mismatch repair genes in HD mice – the benefit lasts up to 20 months of age in a mouse, which would be comparable to about 60 years in humans,' said Professor Yang. 'Our study suggests that these genes are not just disease modifiers, as suggested by the previous studies, but are genetic drivers of Huntington's disease.'

The authors of the study state that understanding more of the genetic components of HD using mouse models could inform further research into treatments, and that the mismatch repair genes make a good candidate for future therapeutics. However, HD in mice differs from HD in humans, so more research will be needed on the function of the mismatch repair genes and their specific roles in human disease.