Scientists Find Mechanism That May Help Restore Frataxin in Friedrich’s Ataxia

Restoring normal frataxin production, the protein missing in Friedrich’s ataxia (FA), may become possible in the future, according to research recently published in the journal PLoS One.

The study is titled “Disruption Of Higher Order DNA Structures In Friedreich’s Ataxia (GAA)n Repeats By PNA Or LNA Targeting,” and was conducted by Helen Bergquist, from the Karolinska Institute in Sweden, and colleagues from other international research institutes.

Friedrich’s ataxia is an incurable pediatric neurodegenerative disease that derives from a mutation in the frataxin protein (caused by repeats of a DNA sequence known as GAA repeat expansion), which impairs the normal expression of this protein.

These expansions cause a substantial reduction in frataxin protein levels and several consequences at the cellular level. Also, low levels of frataxin are responsible for several clinical manifestations, such as ataxia, muscle weakness, abnormal sensitivity of the limbs, several alterations in the structure of certain brain regions such as the cerebellum, and decreased life expectancy.

The presence of GAA repeat expansions blocks the production of frataxin due to the formation of abnormal DNA structures near its gene. Researchers hypothesized whether certain molecules could destroy these DNA structures, thereby opening the possibility of developing new strategies aiming at restoring proper frataxin production.

Bergquist and her colleagues used two types of molecules to target these DNA structures, called PNAs and LNAs. PNAs and LNAs are DNA and RNA mimics, respectively, that can bind to a complementary sequence of DNA or RNA with high strength and specificity. Both types of molecules have the capacity to invade DNA and bind to a specific sequence.

Researchers designed PNAs (peptide nucleic acid) and LNAs (locked nucleic acid) that could recognize the GAA repeats in the frataxin gene and disrupt the associated DNA structures. They observed that both types of molecules could successfully target the abnormal GAA repeats, as well as alter and resolve the DNA structures blocking frataxin production.

The authors concluded: “Our results suggest that DNA targeting … at expanded [GAA] repeats can be employed to examine the possible role of [abnormal] DNA structures in [frataxin] gene silencing and potentially applied to develop new [DNA or RNA] therapeutic strategies in Friedreich’s ataxia disease.”