Preventing the ubiquitin–proteasome-dependent degradation of frataxin, the protein defective in Friedreich's ataxia

Alessandra Rufini, Silvia Fortuni, Gaetano Arcuri, Ivano Condò, Dario Serio, Ottaviano Incani, Florence Malisan, Natascia Ventura, Roberto Testi
2011 Human Molecular Genetics  
Friedreich's Ataxia (FRDA) is a devastating orphan disease, with no specific treatment. The disease is caused by reduced expression of the protein frataxin, which results in mitochondrial defects and oxidative damage. Levels of residual frataxin critically affect onset and progression of the disease. Understanding the molecular mechanisms that regulate frataxin stability and degradation, may therefore be exploited for the design of effective therapeutics. Here we show that frataxin is degraded
more » ... ataxin is degraded by the ubiquitinproteasome system and that K 147 is the critical residue responsible for frataxin ubiquitination and degradation. Accordingly, a K 147 R substitution generates a more stable frataxin. We then disclose a set of lead compounds, computationally selected to target the molecular cleft harboring K 147 , that can prevent frataxin ubiquitination and degradation, and increase frataxin levels in cells derived from FRDA patients. Moreover, treatment with these compounds induces substantial recovery of aconitase activity and ATP levels in FRDA cells. Thus we provide evidence for the therapeutic potential of directly interfering with the frataxin degradation pathway. by guest on February 22, 2016 Downloaded from
doi:10.1093/hmg/ddq566 pmid:21216878 fatcat:gupwrtxamzezfmgn36667j7omy