Preventing Frataxin Degradation May Be Strategy to Manage Friedreich’s Ataxia

Researchers may have found a new therapeutic target for the management of Friedreich’s ataxia.

A study, “E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification Of A Potential Therapeutic Target For Friedreich Ataxia,” was published in the journal Cell Reports.

Friedrich’s ataxia is characterized by reduced expression levels of the protein frataxin due to anomalies in the sequence of the gene encoding this protein. These anomalies consist in repeats of DNA sequences within the gene, and the higher the number of repeats, the sooner the onset of Friedrich’s ataxia and associated complications in patients.

Frataxin plays an important role in the mitochondria, the cell’s powerhouse, so the mutated protein accounts for several symptoms that reflect deficiencies in energy production.

Cells eliminate proteins recurrently, when they are no longer needed or have been working for a while. But if these proteins are present in lower levels than normal, avoiding their degradation could benefit cells.

“Most current therapeutic approaches aim at promoting frataxin [production]; however, molecular characterization of the frataxin degradation pathway suggested the possibility to increase frataxin protein by preventing its degradation,” researchers wrote.

Using a series of experimental techniques, researchers screened several molecules called small interfering RNA (siRNA), which are able to block protein production, searching for those who would block the expression of proteins that control frataxin degradation. They found that treatment of cultured cells with certain siRNAs increased frataxin levels by blocking the proteins that cause its degradation.

Among a few candidates, they identified a molecule called RNF126, an enzyme (protein) that targets frataxin for degradation in cells.

To validate this finding, the team tested a specific siRNA against RNF126 in cells derived from patients with Friedreich’s ataxia. They found that blockade of the RNF126 protein increased frataxin levels.

Taken together, these results indicate the RNF126 protein controls frataxin abundance in cells derived from patients and suggest that inhibiting RNF126 may represent a new therapeutic strategy to promote an increase in frataxin levels and subsequently ameliorate patients’ condition.

“Presently, no effective therapy has been approved to treat [Friedreich’s ataxia],” the researchers wrote. “[Friedreich’s ataxia] patients live with a reduced and insufficient amount of frataxin protein; thus, the main goal of a specific therapy for Friedreich ataxia would be to restore physiological frataxin levels. One possible therapeutic approach to achieve an increase in frataxin levels is to prevent the … degradation of frataxin precursor, thus allowing more frataxin to be imported and processed into mitochondria to generate the mature functional form of frataxin,” the researchers concluded.