title: A new cellular model to follow Friedreich's ataxia development in a time-resolved way.
abstract: Friedreich's ataxia (FRDA) is a recessive autosomal ataxia caused by reduced levels of frataxin (FXN), an essential mitochondrial protein that is highly conserved from bacteria to primates. The exact role of frataxin and its primary function remain unclear although this information would be very valuable to design a therapeutic approach for FRDA. A main difficulty encountered so far has been that of establishing a clear temporal relationship between the different observations that could allow a distinction between causes and secondary effects, and provide a clear link between aging and disease development. To approach this problem, we developed a cellular model in which we can switch off/on in a time-controlled way the frataxin gene partially mimicking what happens in the disease. We exploited the TALEN and CRISPR methodologies to engineer a cell line where the presence of an exogenous, inducible FXN gene rescues the cells from the knockout of the two endogenous FXN genes. This system allows the possibility of testing the progression of disease and is a valuable tool for following the phenotype with different newly acquired markers.
authors.affiliation: Molecular Structure Division, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Vannocci
authors.affiliation: Molecular Structure Division, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Faggianelli
authors.affiliation: Molecular Structure Division, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zaccagnino
authors.affiliation: Molecular Structure Division, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.
authors.forename: Ilaria
authors.initials: I
authors.lastname: della Rosa
authors.affiliation: Department of Basic and Clinical Neurosciences, Kings College London, London NW7 1AA, UK.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Adinolfi
authors.affiliation: Department of Basic and Clinical Neurosciences, Kings College London, London NW7 1AA, UK annalisa.1.pastore@kcl.ac.uk.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D004247:DNA / Q000235:genetics; D018450:Disease Progression; D005621:Friedreich Ataxia / Q000209:etiology* / Q000235:genetics*; D055786:Gene Knockout Techniques; D005818:Genetic Engineering; D057809:HEK293 Cells; D006801:Humans; D033862:Iron-Binding Proteins / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D014162:Transfection; D000096923:Frataxin
chemical_list: D004247:DNA; D033862:Iron-Binding Proteins; D000096923:Frataxin
keywords: Cellular model; Disease development; Frataxin; Genetic models; Zinc fingers