Discovery Could Address Reduced Protein Expression Associated with Friedreich’s Ataxia

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by Alice Melão |

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Friedreich's ataxa finding

Friedreich’s ataxia (FRDA) stems from abnormal DNA code expansions in the Frataxin (FXN) gene that collectively reduce the expression of the FXN protein.

A new study indicates that small RNA and DNA molecules can interact with FXN repeats to block the formation of the abnormal DNA 3D structures that could be behind the reduced protein production.

The findings, in a study titled “Disruption of Higher Order DNA Structures in Friedreich’s Ataxia (GAA) Repeats by PNA or LNA Targeting,” could lead to a better understanding of the disease and therapies that can treat the disease by restoring FXN expression. The research was published in PlosOne,

Ninety-six percent of FRDA cases are associated with too many DNA code repetitions in the FXN gene. This genetic modification can lead to the formation of abnormal DNA 3D structures, which are believed to be partly responsible for reduced expression of the FXN protein. It’s still not clear what underlying mechanism is responsible for this.

Researchers decided to test the hypothesis that abnormal 3D structures can play a role in reduced FXN expression. They looked at two DNA and RNA molecules, locked nucleic acid (LNA) and peptide nucleic acid (PNA), that can interact with the genome.

Their observations confirmed previous evidence that 9, 75, or 115 repeats can lead to abnormal 3D structures of the FXN gene.

They also discovered that the normal 3D structures that are necessary for the proper regulation of gene expression are associated with alterations in gene expression not caused by DNA sequence modification — a phenomenon known as epigenetic modification. These structures are known as intramolecular triplex, or H-DNA.

The results supported the abnormal 3D structure hypothesis, which could explain the FXN silencing mechanism.

Researchers also found that LNA or PNA molecules can interact with DNA structures to block the formation of abnormal 3D structures. This would keep the FXN gene sequence in a state that would allow FXN expression.

“By inhibiting disease-related higher-order DNA structures in the Frataxin gene, such PNA and LNA oligomers may have potential for discovery of drugs aiming at recovering Frataxin expression,” the researchers wrote.

More studies are required to confirm the notion that disrupting the formation of normal 3D structures can impact FXN expression, and to understand the findings’ impact on treating FRDA.