Researchers have identified the molecular mechanism through which loss of frataxin, the protein missing in Friedreich’s ataxia (FA), causes cell damage leading to neurodegeneration, according to a new mouse study.
This finding may prove helpful in designing new therapies to treat Friedreich’s ataxia patients.
The study, “Loss Of Frataxin Activates The Iron/Sphingolipid/PDK1/Mef2 Pathway In Mammals,” was published in the journal eLife.
Friedreich’s ataxia is caused by mutations in the gene encoding frataxin, impairing its production in neurons and leading to neuronal loss and cardiac complications.
In normal cells, frataxin contributes to the synthesis of iron-sulfur proteins in the mitochondria, the cell’s energy powerhouse. Low levels of frataxin limit the production of iron-sulfur proteins, which is associated with reduced energy production, oxidative damage, altered iron metabolism and general mitochondrial dysfunction.
Despite knowing that production of reactive oxygen species (ROS, molecules that are produced as a side effect of the mitochondria’s activity, leading to oxidative damage when levels are too high) and impairment of the production of iron-sulfur proteins are associated with FA, scientists still do not know the exact molecular mechanisms of this relationship.
Using laboratory techniques, researchers eliminated the frataxin gene in mice. This led to iron accumulation in the nervous system and neuronal loss in the brain cortex of the mice, showing that loss of frataxin indeed leads to severe neuronal injury.
The team also observed that one of the consequences triggered by loss of frataxin was the production of a group of fat molecules, called sphingolipids. These molecules then led to the activation of two proteins, PDK1 and Mef2, which triggered neurodegeneration two months before the onset of FA symptoms in mice.
Importantly, researchers found that the same pathways seem to be activated in Friedreich’s ataxia human patients, as well. Indeed, they found that sphingolipid levels and PDK1 activity were also increased in samples of heart tissue from six FA patients.
Taken together, these results suggest that the iron/sphingolipid/PDK1/Mef2 molecular pathway is activated in Friedreich’s ataxia patients and may, therefore, contribute to the pathology of this disease.
“Inhibition of this pathway may not only suppress neurodegeneration, but also prevent or delay cardiomyopathy, the major cause of lethality in [FA],” the authors wrote.
“In sum, this pathway may provide us with therapeutic targets based on antisense oligonucleotide strategies, an option that should be explored,” they said.
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