Human Molecular Genetics, 2002, Vol. 11, No. 23 2989-2996
© 2002 Oxford University Press
Up-regulation of c-Jun N-terminal kinase pathway in Friedreich's ataxia cells
1BioGeM Consortium, Federico II University, Naples, Italy, 2Department of Molecular and Cellular Biology and Pathology and IEOS, CNR, Federico II University, Naples, Italy and 3Department of Neurology, Federico II University, Naples, Italy
Received July 31, 2002; Accepted August 28, 2002
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.
* To whom correspondence should be addressed at: BioGeM s.c.a.r.l. c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università "Federico II", Via S. Pansini, 5, 80131 Napoli Italy. Tel: +39 0817462354; Fax: +39 0817463011; Email: pianese{at}biogem.it
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