#IARC2017 – New Mouse Model of Friedreich’s Ataxia Shows Symptoms Similar to Patients

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A new mouse model of Friedreich’s ataxia, detailed at IARC 2017, exhibits human features of the disease and has the potential to be of ” broad utility” in research into the underlying mechanisms of this common ataxia and ways to fight it.

Its development was discussed at a Thursday session, “Translational Models of Disease,” by Vijayendran Chandran of the David Geffen School of Medicine, University of California at Los Angeles, and the University of Florida’s School of Medicine.

Chandran’s presentation —at the International Ataxia Research Conference running in Pisa, Italy, through Sept. 30 — was titled “Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia.

Friedreich’s ataxia (FA) is caused by genetic defects, or mutations, in the frataxin gene that lead to low frataxin protein levels. Frataxin is a vital component of mitochondria, small organelles inside cells that are responsible for energy production, and which regulate certain metabolic pathways and cellular equilibrium (homeostasis).

Patients with insufficient frataxin often have nervous system damage and movement difficulties, but low levels of this protein affects other systems in the body as well, with the potential for cardiac and metabolic problems.

Animal models that reproduce the full range of FA symptoms are essential to fully understand the disease and its processes, and possibly develop effective therapies.

“Can we recapitulate in animal models several symptoms related to FA?” Chandran asked.

The researcher and his team developed a mouse model of frataxin deficiency that is “inducible,” meaning that researchers can induce FA – through decreased levels of frataxin – at a specific and chosen moment in a study.

This ability allows scientists to “control the onset, progression and potential rescue of disease phenotypes by the modulation of frataxin levels,” the study states.

They induced FA in adult mice and analyzed their phenotype, i.e., investigated if and how accurately the mice manifested disease symptoms and features seen in patients.

Reducing mouse frataxin levels (“knockdown” by almost 90%) resulted in electrophysiological, cellular, biochemical, and structural alterations associated both with heart disease (cardiomyopathy) and nervous system degeneration (dorsal root ganglion, and retinal neuronal degeneration).

Other abnormalities in the knockdown mice were also similar to FA patients, including weight loss, impaired locomotor abilities, ataxia, reduced muscular strength, and death at younger ages. Alterations in gene expression — like poor frataxin protein production — were also evident, much as they are in patients.

According to Chandran, once it was confirmed that the mouse model could mimic disease manifestations seen in FA patients, the next question was “Can we correct these symptoms?”

Frataxin levels in the mice were restored to almost normal levels to determine which disease features might be reversed. Remarkably, the researchers observed a significant recovery of function in a number of them, including gene expression changes, even after the mice had shown significant motor dysfunction.

“At week 24 the rescued group did as good as the control group,” Chandran said in his presentation.

Next, he added, “we wanted to look at the molecular changes, what are the pathways involved in the rescue.”

Researchers found that genes related to the immune system, cell cycle, and apoptosis (cell death) are upregulated, or activated.

“Just by looking into this we observed that immune-related genes are activated early” he said.

According to Chandran, however, the big question is what causes FA symptoms.

In the presentation, he answered this question by noting: “Well, we saw no cell death but [did see] cellular dysfunction, which is sufficient to explain all the behaviors we saw in mice.”

Based on these results, the team concluded in the study that its inducible FA mouse model “is likely to be of broad utility in therapeutic development and in understanding the relative contribution of reversible cellular dysfunction to the devastating phenotypes observed in this condition.”