Inhibitors of p38 — a protein involved in regulating cell growth — show potential for use as therapeutic agents in the treatment of Friedreich’s ataxia (FA), a recent study suggests.
The study, “Identification of p38 MAPK as a novel therapeutic target for Friedreich’s ataxia,” was published in the journal Nature Scientific Reports.
Friedreich’s ataxia — a neuro- and cardio-degenerative disorder — is generally caused by a mutation in the frataxin gene, FXN, that leads to reduced levels of the frataxin protein, which is important for the proper functioning of nerve and muscle cells.
Previous studies have shown that skin cells called fibroblasts derived from patients with FA tend to grow more slowly than normal fibroblasts. These cells undergo a process called senescence in which cell growth stops.
Sometimes these senescent cells release certain molecules called cytokines. These cells adopt what is known as a Senescence Associated Secretion Phenotype (SASP). In order to induce SASP, the activation of a protein called the stress kinase p38 is needed.
In a previous study, researchers discovered that one molecule called gFA11 consistently reversed the growth defect of the FA fibroblasts.
In this most recent study, researchers further explored the effects of gFA11. First, they showed that this molecule reduced the cytokine secretion of these fibroblasts — thereby reducing SASP. This was also accompanied by a normalization of the fibroblast cell structure and other senescence-associated factors.
Next, researchers showed that treatment with gFA11 led to significant changes in the gene expression profile of these fibroblasts. Researchers noticed that the gene-expression profile after gFA11 treatment was very similar to the gene-expression profile induced by a p38 inhibitor called SB203580.
When looking more closely into the p38 protein in the FA fibroblasts, researchers discovered that p38 phosphorylation, which indicates activation of the protein, is increased in cells with the FXN mutation compared with normal cells. This led researchers to suspect p38 plays a role in the development of FA.
In order to further validate this hypothesis, researchers blocked FXN gene expression in normal fibroblasts and showed that it led to an increase in p38 phosphorylation — thereby showing a direct relationship between a lack of frataxin and p38 activation.
Next, researchers treated FA fibroblasts with p38 inhibitors. Results showed that this treatment increased the growth rate of the FA fibroblasts — similar to the results seen with gFA11.
“These data highlight the involvement of the p38 MAPK pathway in the pathogenesis [disease development] of FRDA and the potential use of p38 inhibitors as a treatment for FRDA,” the researchers concluded.
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