Author response: Loss of Frataxin induces iron toxicity, sphingolipid synthesis, and Pdk1/Mef2 activation, leading to neurodegeneration

Le résumé fourni par la source

Friedreich’s ataxia is a disorder in which nerve cells in the spinal cord, cerebellum and dorsal root ganglia progressively die as a person ages. People with this disorder often have difficulties with walking and can eventually develop other problems such as heart disease and diabetes. Mutations in a gene called Frataxin, known as FXN for short, are the primary cause of the disorder. The FXN gene encodes a protein normally found in mitochondria – the structures that are best known for providing energy inside cells. Previous studies suggest that mutations in the FXN gene prevent mitochondria from working normally, which triggers the production of toxic chemicals called reactive oxygen species. However, therapies based on antioxidants (which combat reactive oxygen species) only have limited benefits in patients with Friedreich’s ataxia; this suggests that other mechanisms contribute to the progression of the disease. Mutations in the FXN gene also cause iron to accumulate inside cells, which can be toxic too. However, it remains hotly debated whether or not iron toxicity contributes to Friedreich’s ataxia. Chen et al. set out to identify other mechanisms that can explain the loss of nerve cells seen in Friedreich’s ataxia using fruit flies as an experimental system. Flies without the equivalent of FXN gene accumulated iron in their nervous systems and other tissues, but did not produce more reactive oxygen species. The experiments also revealed that this build-up of iron increased the production of fatty molecules (called sphingolipids), which in turn triggered the activation of two proteins (called Pdk1 and Mef2). Chen et al. then showed that blocking any of these effects could effectively delay the death of nerve cells in the mutant flies. Further experiments showed that boosting the levels of the Mef2 protein in the nerve cells of otherwise normal flies was enough to cause these cells to die. The next step is to see whether the pathway also operates in mice and humans. Future studies could also see if dampening down this pathway could provide new treatments for Friedreich’s ataxia.

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