Src Inhibitors as a New Therapeutic Strategy for Friedreich’s Ataxia

Patrícia Silva, PhD avatar

by Patrícia Silva, PhD |

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A new study led by researchers at University of Rome ‘Tor Vergata’ in Italy recently revealed that inhibitors of the Src protein kinase can represent a potential new therapeutic strategy against Friedreich’s ataxia. The study is entitled “Src inhibitors modulate frataxin protein levels” and was published in the journal Human Molecular Genetics.

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 is caused by a mutation in a gene called frataxin that leads to a defective expression of the frataxin protein. 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.

The frataxin protein is found in the mitochondria, small cellular organelles considered the “powerhouse” of cells, and is involved in iron homeostasis. In Friedreich’s ataxia, important metabolic changes occur, including a mitochondrial redox imbalance and ATP deficiency, which in turn can affect several proteins like the Src tyrosine kinase family.

In the study, researchers assessed whether Src could affect the expression of frataxin protein by phosphorylating it. Phosphorylation is the addition of a phosphate group to a protein by a kinase; this process can alter the protein’s function and activity.

Researchers found that frataxin protein could be phosphorylated by Src kinase, primarily at the tyrosine amino acid Y118. Phosphorylation of frataxin promotes its ubiquitination, which corresponds to the addition of a tag (ubiquitin protein) that marks the protein for degradation. The team found that blocking Src activity through the use of Src inhibitors lead to an accumulation of frataxin protein in human cells, but not on human cells expressing a non-phosphorylatable frataxin-Y118F mutant. Src inhibitors were found to increase frataxin expression in cells derived from Friedreich’s ataxia patients and to rescue the defect in aconitase, a protein involved in iron homeostasis that is deficient in Friedreich’s ataxia.

The team concluded that Src inhibitors are able to induce frataxin accumulation in cells, and suggest that they could be considered a potential therapeutic strategy for Friedreich’s ataxia.