title: Preventing the ubiquitin-proteasome-dependent degradation of frataxin, the protein defective in Friedreich's ataxia.
abstract: 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.
authors.affiliation: Laboratory of Signal Transduction, Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rufini
authors.forename: Silvia
authors.initials: S
authors.lastname: Fortuni
authors.forename: Gaetano
authors.initials: G
authors.lastname: Arcuri
authors.forename: Ivano
authors.initials: I
authors.lastname: Condò
authors.forename: Dario
authors.initials: D
authors.lastname: Serio
authors.forename: Ottaviano
authors.initials: O
authors.lastname: Incani
authors.forename: Florence
authors.initials: F
authors.lastname: Malisan
authors.forename: Natascia
authors.initials: N
authors.lastname: Ventura
authors.forename: Roberto
authors.initials: R
authors.lastname: Testi
mesh_terms: D000154:Aconitate Hydratase / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D005621:Friedreich Ataxia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000096923:Frataxin
chemical_list: D000154:Aconitate Hydratase; D000255:Adenosine Triphosphate; D033862:Iron-Binding Proteins; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin; D000096923:Frataxin