Researchers at Tufts University, USA have discovered a mechanism that could be used to develop therapeutic strategies to reverse the genetic expansion causing Friedreich’s ataxia. Published in the Proceedings of the National Academy of Sciences, the researchers report that the triplet expansion of DNA that causes the disease could potentially be reversed by targeting the process of DNA replication that naturally contracts the expansion in living tissues. 

Friedreich’s ataxia is a rare genetic disease affecting around 1 in 50,000 people in the UK. It’s a progressive neurodegenerative disorder, typically with onset before 20 years of age and results in difficulty walking, a loss of sensation in the arms and legs, and impaired speech caused by degeneration of nerve tissue in the spinal cord.

Friedreich’s ataxia is caused by an expansion of the triplet code GAA in the FXN gene that encodes for frataxin – a protein required for the proper function of mitochondria. In sufferers, GAA is repeated more than 70 times (commonly hundreds of times), whereas healthy individuals have 8-34 repeats and carriers have 35-70 repeats. The huge repeat expansion affects how the cells “read” the FXN gene, and by not being able to make the frataxin protein properly, it makes it difficult for mitochondria to work as they should.

The GAA repeats cause DNA to be unstable and continuously expand and contract in number. Understanding exactly how this process works – especially contraction – could be an important point for developing a strategy for battling this disease. The repeats can cause other mutations in surrounding DNA and make chromosomes very fragile, leading them to break into pieces or rearrange themselves.

The researchers at Tufts University used yeast (Saccharomyces cerevisiae) to develop an experimental system that could measure the effects of different interventions on contractions of DNA repeats. Their results showed that contractions usually occurred during DNA replication, specifically during “lagging strand synthesis”. When the DNA double helix undergoes replication, one strand (the leading strand) is replicated continuously, while the other (the lagging strand) is replicated in fragments. It’s more complicated to replicate the lagging strand because of these fragments, and this limits the rate at which the DNA can be replicated.

The huge GAA repeat causes the unstable DNA to form a triple helix during replication, which prevents the replication machinery from working correctly. The replication machinery must jump over this triple helix hurdle, and so the resulting replicated DNA strand contains fewer GAA repeats and, therefore, contraction. 

These results provide clues into the mechanism of DNA repeat instability in Friedreich’s ataxia, and the team hope that their discovery will become a starting point to develop potential therapeutic strategies to help stabilise the DNA and reduce the repetition in tissues down to levels found in healthy individuals.