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.

Cherubini, F., Serio, D., Guccini, I., Fortuni, S., Arcuri, G., Condo', I., et al. (2015). Src inhibitors modulate frataxin protein levels. HUMAN MOLECULAR GENETICS, 24(15), 4296-4305 [10.1093/hmg/ddv162].

Src inhibitors modulate frataxin protein levels

SERIO, DARIO;GUCCINI, ILARIA;ARCURI, GAETANO;CONDO', IVANO;RUFINI, ALESSANDRA;TESTI, ROBERTO;MALISAN, FLORENCE
2015-08-01

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.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/04 - Patologia Generale
English
Con Impact Factor ISI
Cherubini, F., Serio, D., Guccini, I., Fortuni, S., Arcuri, G., Condo', I., et al. (2015). Src inhibitors modulate frataxin protein levels. HUMAN MOLECULAR GENETICS, 24(15), 4296-4305 [10.1093/hmg/ddv162].
Cherubini, F; Serio, D; Guccini, I; Fortuni, S; Arcuri, G; Condo', I; Rufini, A; Moiz, S; Camerini, S; Crescenzi, M; Testi, R; Malisan, F
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/117428
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