title: Highly specific ubiquitin-competing molecules effectively promote frataxin accumulation and partially rescue the aconitase defect in Friedreich ataxia cells.
abstract: Friedreich ataxia is an inherited neurodegenerative disease that leads to progressive disability. There is currently no effective treatment and patients die prematurely. The underlying genetic defect leads to reduced expression of the mitochondrial protein frataxin. Frataxin insufficiency causes mitochondrial dysfunction and ultimately cell death, particularly in peripheral sensory ganglia. There is an inverse correlation between the amount of residual frataxin and the severity of disease progression; therefore, therapeutic approaches aiming at increasing frataxin levels are expected to improve patients' conditions. We previously discovered that a significant amount of frataxin precursor is degraded by the ubiquitin/proteasome system before its functional mitochondrial maturation. We also provided evidence for the therapeutic potential of small molecules that increase frataxin levels by docking on the frataxin ubiquitination site, thus preventing frataxin ubiquitination and degradation. We called these compounds ubiquitin-competing molecules (UCM). By extending our search for effective UCM, we identified a set of new and more potent compounds that more efficiently promote frataxin accumulation. Here we show that these compounds directly interact with frataxin and prevent its ubiquitination. Interestingly, these UCM are not effective on the ubiquitin-resistant frataxin mutant, indicating their specific action on preventing frataxin ubiquitination. Most importantly, these compounds are able to promote frataxin accumulation and aconitase rescue in cells derived from patients, strongly supporting their therapeutic potential.
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy; Fratagene Therapeutics Ltd., 22 Northumberland Rd., Dublin, Ireland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rufini
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cavallo
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy.
authors.forename: Ivano
authors.initials: I
authors.lastname: Condò
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy; Fratagene Therapeutics Ltd., 22 Northumberland Rd., Dublin, Ireland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Fortuni
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: De Martino
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy.
authors.forename: Ottaviano
authors.initials: O
authors.lastname: Incani
authors.affiliation: Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy.
authors.forename: Almerinda
authors.initials: A
authors.lastname: Di Venere
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Benini
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy.
authors.forename: Damiano Sergio
authors.initials: DS
authors.lastname: Massaro
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Arcuri
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Serio
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy.
authors.forename: Florence
authors.initials: F
authors.lastname: Malisan
authors.affiliation: Laboratory of Signal Transduction, Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Via Montpellier 1, Rome 00133, Italy; Fratagene Therapeutics Ltd., 22 Northumberland Rd., Dublin, Ireland. Electronic address: roberto.testi@uniroma2.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Testi
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D005453:Fluorescence; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D033862:Iron-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009154:Mutation; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D000096923:Frataxin
chemical_list: D000154:Aconitate Hydratase; D033862:Iron-Binding Proteins; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D000096923:Frataxin
keywords: Frataxin; Friedreich ataxia; Orphan drug development; Ubiquitin