The severe reduction in mRNA and protein levels of the mitochondrial protein 
frataxin, encoded by the X25 gene, causes Friedreich ataxia (FRDA), the most 
common form of recessive hereditary ataxia. Increasing evidence underlines the 
pathogenetic role of oxidative stress in this disease. We generated an in vitro 
cellular model of regulated human frataxin overexpression. We identified, by 
differential display technique, the mitogen activated protein kinase kinase 4 
mRNA down regulation in frataxin overexpressing cells. We studied the stress 
kinases pathway in this cellular model and in fibroblasts from FRDA patients. 
Frataxin overexpression reduced c-Jun N-terminal kinase phosphorylation. 
Furthermore, exposure of FRDA fibroblasts to several forms of environmental 
stress caused an up regulation of phospho-JNK and phospho-c-Jun. To understand 
if this susceptibility results in cell death, we have investigated the 
involvement of caspases. A significantly higher activation of caspase-9 was 
observed in FRDA versus control fibroblasts after serum-withdrawal. Our findings 
suggest the presence, in FRDA patient cells, of a 'hyperactive' stress signaling 
pathway. The role of frataxin in FRDA pathogenesis could be explained, at least 
in part, by this hyperactivity.