Study in Cell Models Reveals Potential Therapeutic Strategy for Friedreich’s Ataxia

A recent study published in the journal Pharmacological Research revealed a new potential therapeutic strategy against Friedreich’s ataxia in cell models. The study is entitled “Targeting lipid peroxidation and mitochondrial imbalance in Friedreich’s ataxia” and was led by researchers at the UCL Institute of Neurology in the United Kingdom.

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. Disease onset is usually during childhood or adolescence and the disorder leads to progressive disability, dependence on a wheelchair and reduced life expectancy. Currently, there is no effective approved treatment for the disease.

Friedreich’s ataxia is caused by a mutation in a gene called frataxin (FXN) that leads to a defective expression of the frataxin protein. This protein is found in the mitochondria, small cellular organelles considered the “powerhouse” of cells were energy is produced. Frataxin is involved in the biogenesis of iron-sulphur clusters and iron homeostasis.

Decreased frataxin expression in Friedreich’s ataxia patients leads to iron accumulation in the mitochondria and increased sensitivity to oxidative stress, which can ultimately lead to cell death. One of the treatment approaches for the disorder is based on the decrease of hypersensitivity to reactive oxygen species (ROS), molecules that result from oxygen metabolism and that can induce significant damage to cell structures triggering cell death.

In the study, researchers assessed the possibility of using protective compounds against cell death. They tested two different types of compounds: deuterised poly-unsaturated fatty acids (dPUFAs), which have been shown to protect cells from damage caused by the oxidative degradation of lipids (lipid peroxidation), and Nrf2-inducers, which are able to trigger the Nrf2 antioxidant pathway. The compounds were tested in two different cell lines from Friedreich’s ataxia mouse models, YG8R and KIKO.

Researchers found that both dPUFAs and Nrf2-inducers were able to prevent the sensitivity to oxidative stress, and subsequent lipid peroxidation and cell death, in the two cells lines tested. The team also found that the two cell lines have a different degree of mitochondrial dysfunction, where YG8R has a mild impairment while KIKO seems to suffer a more severe effect. The authors suggest that these differences might be linked to the different genetic background of the lines.

In conclusion, the team proposes a Friedreich’s ataxia treatment strategy based on the employment of compounds that prevent oxidation effects by either reducing lipid peroxidation or activating the Nrf2 antioxidant pathway. The authors also emphasize that the two mouse cell models used could recapitulate the phenotypic variability observed in Friedreich’s ataxia patients, and propose that they could represent useful tools for further research on the disorder.