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Hum Mol Genet. 2015 Aug 1;24(15):4296-305. doi: 10.1093/hmg/ddv162. Epub 2015 May 6.

Src inhibitors modulate frataxin protein levels.

Author information

1
Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy.
2
Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy, Fratagene Therapeutics Ltd, 22 Northumberland Rd, Dublin, Ireland and.
3
Department of Cell Biology and Neurosciences, Italian National Institute of Health, Viale Regina Elena, 299, 00161 Rome, Italy.
4
Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome 'Tor Vergata', Via Montpellier 1, 00133 Rome, Italy, malisan@med.uniroma2.it.

Abstract

Defective expression of frataxin is responsible for the inherited, progressive degenerative disease Friedreich's Ataxia (FRDA). There is currently no effective approved treatment for FRDA and patients die prematurely. Defective frataxin expression causes critical metabolic changes, including redox imbalance and ATP deficiency. As these alterations are known to regulate the tyrosine kinase Src, we investigated whether Src might in turn affect frataxin expression. We found that frataxin can be phosphorylated by Src. Phosphorylation occurs primarily on Y118 and promotes frataxin ubiquitination, a signal for degradation. Accordingly, Src inhibitors induce accumulation of frataxin but are ineffective on a non-phosphorylatable frataxin-Y118F mutant. Importantly, all the Src inhibitors tested, some of them already in the clinic, increase frataxin expression and rescue the aconitase defect in frataxin-deficient cells derived from FRDA patients. Thus, Src inhibitors emerge as a new class of drugs able to promote frataxin accumulation, suggesting their possible use as therapeutics in FRDA.

PMID:
25948553
DOI:
10.1093/hmg/ddv162
[Indexed for MEDLINE]

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