Researchers Suggest New Potential Therapeutic Approach for Friedreich’s Ataxia Based on Incretin Analogs

Patrícia Silva, PhD avatar

by Patrícia Silva, PhD |

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A new study recently published in the journal Neurology revealed a potential novel therapeutic approach for Friedreich’s ataxia based on analogs of incretin, a metabolic hormone that stimulates insulin secretion. The study is entitled “Study of beta cells and neurons indicate incretin analogs as potential therapeutics for Friedreich’s ataxia” and was performed by researchers at the Université Libre De Bruxelles, the Université Catholique de Louvain, Brussels, Belgium and the Hannover Medical School, Germany.

Friedreich’s ataxia is a rare inherited neurodegenerative disease characterized by progressive damage of the nervous system with degeneration of the spinal cord and peripheral nerves that leads to muscle weakness, sensory loss, balance deficits and lack of voluntary coordination of muscle movements. The disease onset is usually during childhood or adolescence and the disorder leads to progressive disability, dependence on a wheelchair and reduced life expectancy.

Friedreich’s ataxia is caused by a mutation in a gene called frataxin (FXN) that causes a reduction in messenger RNA and subsequent impaired expression of the frataxin protein. This protein is found in the mitochondria, small cellular organelles considered the “powerhouse” of cells, being involved in iron-sulfur (Fe-S) cluster biogenesis, which are cofactors vital for the proper functioning of several proteins. Friedreich’s ataxia is characterized by mitochondrial dysfunction, disruption of iron homeostasis and ultimately cell death.

In this study, researchers analyzed the pathogenic mechanisms linked to Friedreich’s ataxia and frataxin deficiency and searched for potential therapeutic approaches using relevant cellular models for the disease — neurons and beta cells (cells in the pancreas responsible for the production, storage and release of the hormone insulin into the bloodstream).

The research team stimulated the differentiation of control and Friedreich’s ataxia induced pluripotent stem cells (iPSC) into neurons. Regarding beta cells, researchers silenced the expression of frataxin and pro-apoptotic factors (factors that contribute to apoptosis, also known as programmed cell death) by a technique called RNA interference. The mitochondrial H2O2 production, apoptosis, glutathione redox state and the expression of frataxin, pro-apoptotic factors, Fe-S proteins and mitochondrial superoxide dismutase 2 (SOD2, a protein that transforms superoxide into H2O2 and oxygen) was evaluated. As pharmacological interventions, the team tested scavengers of reactive oxygen species (ROS, which can cause significant cell damage), and inducers of cAMP (a molecule important for intracellular signal transduction) such as forskolin and exendin (an analog of incretin).

Researchers found that in Friedreich’s ataxia neurons, the levels of Fe-S proteins were decreased, while SOD2 expression increased. Beta cells lacking frataxin exhibited a higher mitochondrial H2O2 production and glutathione oxidation. Beta cells also induced the expression of pro-apoptotic proteins (DP5, Puma, and Bim). Apoptosis was found to be higher in frataxin-depleted cells and it could be reduced by ROS scavengers. Treatment with either forskolin or exendin prevented apoptosis, stabilized mitochondrial oxidative status and upregulated frataxin levels by 1.5 to 2 fold in both neurons and beta cells. Treated Friedreich’s ataxia neurons also exhibited increased levels of Fe-S proteins and a decrease in SOD2.

The research team concluded that frataxin depletion causes mitochondrial oxidative stress and apoptosis activation in vulnerable cells like neurons and beta cells, and that this phenomenon can be prevented by cAMP induction leading to an increase in frataxin levels. Researchers propose that incretin analogs could offer a novel therapeutic approach for Friedreich’s ataxia, having initiated a proof-of-concept trial to determine whether these drugs can also safely induce frataxin in vivo.