Symptoms of FA Largely Reversed in New Mouse Model, Study Shows

Iqra Mumal, MSc avatar

by Iqra Mumal, MSc |

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UCLA scientists have found that many early symptoms of Friedreich’s ataxia (FA) can be reversed, according to research they conducted in a new mouse model of the disease.

Their study, titled “Inducible and reversible phenotypes in a novel mouse model of Friedreich’s Ataxia,” was published in the journal eLife.

Friedreich’s ataxia is caused by mutations in the FXN gene, which leads to reduced levels of frataxin, a mitochondrial protein. This can lead to major damage to the nervous system, causing loss of coordination and muscle weakness. Symptoms can also include cardiovascular abnormalities, vision impairment, and diabetes.

Although researchers have created animal models of FA, the models are only mildly symptomatic or unable to capture the complete disease profile of FA. As a result, better animal models were needed to answer the many questions that remain about the disease.

“The lack of treatments for Friedreich’s ataxia has been frustrating for many and has been, in part, due to the lack of good animal models of the disease,” Dr. Daniel Geschwind, a UCLA professor of neurology and psychiatry, and senior author of the new study, said in a press release.

Geschwind’s lab set out to develop a mouse model of FA that demonstrates symptoms similar to human FA patients. They created an inducible mouse model of FA, which allows researchers to tightly control the production of frataxin.

This mouse model allowed the team to investigate whether the disease symptoms are reversible.

Researchers reduced the levels of frataxin protein in mice for 12 weeks, and found that the mice developed symptoms similar to humans with FA, such as weight loss, ataxia, impaired walking, hunched backs, and reduced muscular strength.

And when the researchers allowed the levels of the protein to increase, they found that most of the symptoms disappeared.

“Remarkably, most of the dysfunction we were seeing in the mice was reversible even after the mice showed substantial neurologic dysfunction,” Geschwind said. “We were very surprised by the extent to which the mice improved, since we had assumed that this degree of behavioral dysfunction would be due to cell loss.”

Researchers also conducted gene expression analysis, which helps determine how levels of expression of different genes change due to disease. This can help them determine which cellular pathways are altered in mice with reduced levels of frataxin.

The researchers discovered that pathways involved in insulin signaling, fat metabolism, and the cellular cycle, among others, were significantly altered.

This improved understanding of how a deficiency of frataxin protein leads to the disease and its symptoms may help in the development of potential therapeutic targets or biomarkers for Friedreich’s ataxia.

“We characterize a new, inducible model of Fxn deficiency and provide multiple lines of evidence that Fxn knockdown in adult mice leads to clinical–pathological features parallel to those observed in [Friedreich’s ataxia] patients,” the researchers wrote in the study.

Restoring frataxin to the mice demonstrated a reversal in many symptoms, indicating that clinical symptoms are a result of reversible cellular dysfunction, they added.