Stabilizing mRNA Can Increase Frataxin Levels, Cell Study Shows

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

Share this article:

Share article via email
An illustration shows a vertical DNA strand.

Targeting the end regions of FXN mRNA – the intermediary molecule used to make frataxin – may allow cells to make more of this protein, whose absence causes Friedreich’s ataxia, a new study shows.

“We demonstrated a novel approach to increase intracellular levels of FXN mRNA and protein based on targeting of mRNA ends,” its researchers wrote.

The study, “Targeting 3′ and 5′ untranslated regions with antisense oligonucleotides to stabilize frataxin mRNA and increase protein expression,” was published in Nucleic Acids Research.

Friedreich’s ataxia is caused by mutations in the FXN gene, which codes for the protein frataxin. In most cases, disease-causing mutations in FXN don’t actually change the instructions for making the frataxin protein itself; instead, cells just make it at much lower levels than healthy cells.

Recommended Reading
An illustration offers a close-up view of a synapse, the site where nerve impulses are transmitted between cells.

Thinning of Eye’s Retina May Be Useful Marker of FA Progression

As low frataxin levels are what ultimately cause Friedreich’s ataxia, a theoretical strategy to treat the disease would be to increase this protein’s production in cells. A team led by scientists at the University of Alabama at Birmingham have shown that it’s possible to do this by targeting FXN mRNA.

When a gene like FXN is “read,” the cell uses the gene sequence as a template to make mRNA (messenger RNA). The mRNA, basically a copy of the code for that gene, is sent to ribosomes, the cells’ protein-making machinery that “reads” the code to create a protein.

Importantly, mRNA is not an especially stable molecule and mutated FXN mRNA is thought to be especially unstable. This means there’s often little time for ribosomes to “read” the message and create a protein.

A molecule of mRNA contains the whole genetic sequence for a given gene, but it also contains additional sequences at either end called the 3-prime and 5-prime untranslated regions, which are important for regulating how the mRNA is processed and transported within the cell.

Here, the researchers showed that targeting the 3-prime and 5-prime untranslated regions of FXN mRNA using certain oligonucleotides – small pieces of DNA with a specific sequence – can increase the mRNA’s stability.

This allows ribosomes to read the mRNA more times, ultimately allowing for more frataxin protein to be produced. A single mRNA molecule can be used to make several hundreds of protein copies.

In a battery of tests using cells derived from Friedreich’s ataxia patients, the researchers showed that treatment with these oligonucleotides could increase FXN mRNA stability and frataxin protein levels without any apparent changes to the cells’ DNA. The scientists also showed that combining oligonucleotides to simultaneously target both the 3-prime and 5-prime untranslated regions led to a more pronounced effect.

While oligonucleotide treatment increased levels of FXN mRNA by four and five times, the effect on frataxin levels was more modest; it increased about 2.5 times at its highest.

This may suggest that the actual reading of FXN mRNA by ribosomes is impaired in people with Friedreich’s ataxia, the researchers noted. It is also possible that the binding of the oligonucleotides to the 3-prime region reduces the protein-making machinery’s effectiveness.

“These results identify a novel approach toward [increasing] steady-state mRNA levels via oligonucleotide-mediated end targeting that may be of significance to any condition resulting from” lower mRNA levels, the researchers concluded.