Journal
HUMAN MOLECULAR GENETICS
Volume 20, Issue 7, Pages 1253-1261Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddq566
Keywords
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Funding
- Ataxia UK
- Friedreich's Ataxia Research Alliance (FARA)
- National Ataxia Foundation (NAF)
- Telethon Italia
- Agenzia Spaziale Italiana
- Fondazione Santa Lucia
- Association Francaise de l'Ataxie de Friedreich (AFAF)
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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 by the ubiquitin-proteasome 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 adenosine-5'-triphosphate levels in FRDA cells. Thus, we provide evidence for the therapeutic potential of directly interfering with the frataxin degradation pathway.
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