Discovery in Plants May Help Uncover Genetic Mechanism, Potential Therapies for Friedreich’s Ataxia

A discovery made in plants may shed light on the genetic mechanism underlying Friedreich’s ataxia (FA) and open the door to new ways to treat the disease, a study reports.

Looking at genetic alterations in plants similar to the ones found in the FXN gene in humans with Friedreich’s ataxia, researchers discovered how the expansion of DNA repeats within a gene leads to the shutdown of its expression, or protein production, and consequent disease manifestations.

The study, “RNA-Dependent Epigenetic Silencing Directs Transcriptional Downregulation Caused by Intronic Repeat Expansions,” was published in the journal Cell.

Friedreich’s ataxia is caused by mutations in the FXN gene that greatly reduce the amount of frataxin protein being produced inside cells and — by as-yet unknown mechanisms — leads to the symptoms of the disease.

A segment of the FXN gene contains a DNA stretch called the GAA trinucleotide, which is repeated multiples times in a row. Most people carry a low number of these repeats, fewer than 12; in some, however, the gene may have up to 33 repeats and still be considered normal.

But in people with FA, the GAA segment is repeated from 66 to more than 1,000 times. Strikingly, the length of the trinucleotide repeat seems to correlate with disease progression. The longer the stretch of repeats, the younger the age at symptom onset, and the greater the severity and speed of progression.

Now a team of researchers at the Monash School of Biological Sciences in Australia might have figured out why excessive numbers of GAA repeats mess up the expression of the FXN gene in Friedreich’s ataxia.

Studying a parallel case of genetic deficiency in a plant laboratory model called Arabidopsis, they show that repeat expansions within a gene lead to the accumulation of small genetic messengers called small RNAs.

These small RNAs end up triggering a mechanism known as epigenetic silencing, which shut downs the expression of the gene harboring the repeats.

“We have pointed at least 11 different genes in this process and it is remarkable that if we perturb these genes we can abolish the negative impacts of this mutation — at least in plants,” Sridevi Sureshkumar, PhD, a research fellow at the Monash School of Biological Sciences and first author of the study, said in a press release.

While there have been efforts to develop therapies that directly counteract the silencing of FXN gene, such as gene therapy or RNA-based treatments, this remains difficult in part because it has been unclear how the repeats lower FXN expression.

Now that researchers have found out why similar repeats occur in a gene in plants, this may well clear the way for developing new therapies to treat Friedreich’s ataxia.

“This research has major implications for our understanding of how the genetic mutation that underlies Friedreich ataxia, leads to damage of the nervous system and thus symptoms of this condition,” said Martin Delatycki, MD, PhD, a clinician and researcher from Murdoch Children’s Research Institute who has studied Friedreich’s ataxia for several years.

“This may lead to treatments that are desperately needed for this devastating disorder,” he said.

The study is a good example of how scientific discoveries done in distant organisms can help us learn more about how our own body works and why it becomes sick.

“Small RNAs were first discovered in plants, but later found to play important roles in all organisms including humans,”  said Detlef Weigel, PhD, a renowned plant biologist and foreign member of Royal Society from the Max Planck Institute in Germany.

As a result, this plant-based study has managed to uncover an important link to a phenomenon that is highly relevant to a human genetic disease. And this was only possible “because experiments can be conducted in plants that are simply not possible in humans,” Weigel said.