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

Hum Mol Genet. 2011 Apr 1;20(7):1253-61. doi: 10.1093/hmg/ddq566. Epub 2011 Jan 7.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aconitate Hydratase / genetics
  • Aconitate Hydratase / metabolism
  • Adenosine Triphosphate / genetics
  • Adenosine Triphosphate / metabolism
  • Amino Acid Substitution
  • Frataxin
  • Friedreich Ataxia / drug therapy
  • Friedreich Ataxia / genetics
  • Friedreich Ataxia / metabolism*
  • HEK293 Cells
  • Humans
  • Iron-Binding Proteins / genetics
  • Iron-Binding Proteins / metabolism*
  • Mutation, Missense
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism*
  • Ubiquitin / genetics
  • Ubiquitin / metabolism*
  • Ubiquitination*


  • Iron-Binding Proteins
  • Ubiquitin
  • Adenosine Triphosphate
  • Proteasome Endopeptidase Complex
  • Aconitate Hydratase