Researchers at Miguel Hernandez University and the University of Murcia in Spain have recently published in the journal Experimental Cell Research their results on genetic and epigenetic factors linked to Friedreich’s ataxia. The study is entitled “Novel aberrant genetic and epigenetic events in Friedreich׳s ataxia.”
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.
The disease is caused by a mutation in a gene called frataxin that leads to 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, involved in iron homeostasis.
It is known that neurodegenerative diseases are the result of a complex interaction between genetic and epigenetic factors. Epigenetics refers to external modifications to DNA that do not change the DNA sequence but can control gene expression. Apart from frataxin, no other possible genes have been linked to the Friedreich’s ataxia.
Human periodontal ligament cells, which attach the teeth to their bony socket, have been previously found to express low levels of frataxin in Friedreich’s ataxia patients and increased levels of apoptotic (cell death) markers such as caspase 3 when compared to healthy controls. In this study, researchers analyzed gene expression in human periodontal ligament cells from Friedreich’s ataxia patients and healthy individuals. Frataxin expression and its pattern of methylation (epigenetic regulation mechanism where a methyl group is added to nucleotides in the DNA molecule) were assessed.
Researchers found that cells from Friedreich’s ataxia patients have increased expression of apoptosis-related genes, iron-related genes and oxidative stress-related genes. Brain-derived neurotrophic factor, neuregulin 1 and miR-132 were also found to be upregulated in Friedreich’s ataxia cells. The frataxin gene was found to be hypermethylated in Friedreich’s ataxia cells and of the three known DNA methyltransferases, DNMT1 had the highest expression in comparison to cells from healthy controls.
Remarkably, the team found that cells from Friedreich’s ataxia patients cultured in the presence of idebenone (an analog of coenzyme Q10 antioxidant) and deferiprone (an iron chelating agent) exhibited a decrease in the expression of apoptosis-related genes and an increase in the expression of antioxidant genes and frataxin. The results suggest that idebenone and deferiprone can, to some extent, normalize the altered gene expression seen in Friedreich’s ataxia.
The research team concluded that frataxin is not the only gene affected in this disorder as several other genes involved in iron homeostasis, oxidative stress, cell cycle and apoptosis also have an altered expression in cells from Friedreich’s ataxia patients.