title: A cellular model for Friedreich Ataxia reveals small-molecule glutathione peroxidase mimetics as novel treatment strategy.
abstract: Friedreich Ataxia (FRDA), the most prevalent of the inherited ataxias, is a multi-systemic disease with loss of sensory neurons and life-threatening hypertrophic cardiomyopathy as its most severe manifestations. Reduced levels of the mitochondrial protein frataxin lead to cell-damaging oxidative stress and consequently FRDA is considered as a model for more common neurodegenerative disorders in which reactive radicals and oxidative stress are involved. We have developed a cellular assay system that discriminates between fibroblasts from FRDA patients and unaffected donors on the basis of their sensitivity to pharmacological inhibition of de novo synthesis of glutathione. With this assay we observed that supplementation with selenium effectively improved the viability of FRDA fibroblasts, indicating that basal selenium concentrations are not sufficient to allow an adequate increase in the activity of certain detoxification enzymes (such as GPX). Furthermore, we characterized potential drug candidates and found that idebenone, a mitochondrially localized antioxidant that ameliorates cardiomyopathy in FRDA patients, as well as other lipophilic antioxidants protected FRDA cells from cell death. Our results also demonstrate for the first time that small-molecule GPX mimetics have potential as a novel treatment strategy for Friedreich Ataxia and presumably also for other neurodegenerative diseases with mitochondrial impairment.
authors.affiliation: MyoContract Ltd, Hammerstrasse 25, CH-4410 Liestal, Switzerland.
authors.forename: Matthias L
authors.initials: ML
authors.lastname: Jauslin
authors.forename: Thomas
authors.initials: T
authors.lastname: Wirth
authors.forename: Thomas
authors.initials: T
authors.lastname: Meier
authors.forename: Fabrice
authors.initials: F
authors.lastname: Schoumacher
mesh_terms: D016227:Benzoquinones / Q000378:metabolism; D001681:Biological Assay; D032701:Biomimetics; D003067:Coenzymes; D005347:Fibroblasts; D005621:Friedreich Ataxia / Q000201:enzymology* / Q000235:genetics* / Q000628:therapy; D005978:Glutathione / Q000096:biosynthesis; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D003067:Coenzymes; D014451:Ubiquinone; D005979:Glutathione Peroxidase; C024989:coenzyme Q10; D005978:Glutathione; C036619:idebenone