Genetic Switch Model Gives Scientists a Time Window into Friedreich’s Ataxia Development

Genetic Switch Model Gives Scientists a Time Window into Friedreich’s Ataxia Development

Researchers have created a cell model that will allow the study of molecular changes that result from the loss of the Friedreich’s ataxia (FA) protein frataxin at different time points in development. The model will likely advance knowledge into the molecular consequences of frataxin loss, and will allow both the identification of drug targets for the disease as well as more in-depth analyses of drug actions in Friedreich’s ataxia.

The study, “Time-resolved functional analysis of acute impairment of frataxin expression in an inducible cell model of Friedreich ataxia,” was published in the journal Biology Open.

Although studies have tried to establish what the frataxin protein really does, researchers are still uncertain about the role it plays in the body. One of the things most researchers agree on is that the protein likely contributes to the production of iron-sulfur clusters, as well as proteins holding those clusters.

When researchers grow cells isolated from patients in the lab, however, they don’t find problems with iron-sulfur cluster proteins and enzymes, and they suspect the timing of various molecular events is crucial in understanding how a lack of frataxin leads to the symptoms of Friedreich’s ataxia.

Disease models using animals or animal cells have been difficult to create, since many models do not mirror all the symptoms and molecular features of the disease. Researchers at Friedrich Schiller University Jena in Germany created a new model using cells isolated from mice.

They first engineered mice with a switch incorporated into their DNA. The switch allowed researchers to turn off either one or both frataxin gene copies when researchers studied cells, isolated from the mice, in the lab.

When both gene copies were turned off, the cells had lower cell division rates, lower levels of the iron-sulfur containing enzyme aconitase, and lower oxygen consumption rates. The production of reactive oxygen species was also increased.

In contrast, switching off only one frataxin gene copy did not lead to any such changes. The research team also noted that the changes varied with time, and could identify early and late molecular events following the loss of frataxin.

“This murine [FA] model might be useful for testing new pharmacological candidates to delay or cure the metabolic features following loss of frataxin function and helps us to get a first impression on how they might influence FA pathogenesis,” the researchers wrote.

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