Neurodegeneration in Friedreich’s ataxia can be independent of faulty mitochondria and oxidant molecules. Rather, researchers at Baylor College of Medicine in Houston, Texas, demonstrated that iron toxicity contributed to disease processes in a fruit fly model of the disease.
The study, “Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration,” published in the journal eLife, underscores that defective iron processing needs to be further evaluated as a factor contributing to the development of Friedreich’s ataxia.
Frataxin, the protein whose mutation causes the crippling disease, is located in mitochondria — an energy factory that can also produce damaging oxidative molecules, so-called reactive oxygen species, in the process. This has led researchers to believe that Friedreich’s ataxia arises as a consequence of faulty energy production, which leads to an excess of oxidizing molecules.
But this theory is not supported by everyone, and researchers look for alternative explanations for the neuron death that characterizes the disease. The Baylor team homed in on iron, a trace element that has been shown to accumulate in both animal models and people with Friedreich’s ataxia.
Whether iron accumulates in the central nervous system, including the brain and spinal cord, is not at all established. Scientists are also still not sure whether any potential accumulation of iron could contribute to disease processes.
Using a fruit fly model of the disease, researchers studied the effects of a frataxin mutation that, despite interrupting mitochondrial processes, did not give rise to increased levels of reactive oxygen species but did cause excessive iron deposits in the central nervous system.
Although the apparent differences between humans and fruit flies might seem to make them poor models of human disease, about 75 percent of human disease genes have a similar version in the flies, and molecular processes between the two species are astonishingly similar.
The high iron levels in the flies turned out to be toxic, and triggered the activation of molecular pathways that contributed to the death of neurons. When researchers dampened the toxicity by blocking key steps in these pathways, neurodegeneration was slowed.