Journal of Neurology

, Volume 256, Supplement 1, pp 18–24

Multicellular models of Friedreich ataxia

Article

Abstract

Patients with Friedreich ataxia (FRDA) have severely reduced levels of the mitochondrial protein frataxin, which results from a large GAA triplet-repeat expansion within the frataxin gene (FXN). High evolutionary conservation of frataxin across species has enabled the development of disease models of FRDA in various unicellular and multicellular organisms. Mouse models include classical knockout models, in which the Fxn gene is constitutively inactivated, and knock-in models, in which a GAA repeat mutation or the conditional allele is inserted into the genome. Recently, “humanised” GAA repeat expansion mouse models were obtained by combining the constitutive knockout with the transgenic expression of a yeast artificial chromosome carrying the human FRDA locus. In lower organisms such as Caenorhabditis elegans and Drosophila, straight-forward and conditional RNA interference technology has provided an easy way to knock down frataxin expression. Conditional mouse models have been used for pre-clinical trials of potential therapeutic agents, including idebenone, MnTBAP (a superoxide dismutase mimetic), and iron chelators. Various models of FRDA have shown that different, even opposite, phenotypes can be observed, depending on the level of frataxin expression. Additional studies with animal models will be essential for an enhanced understanding of the disease pathophysiology and for the development of better therapies.

Key words

mouse C. elegans Drosophila frataxin disease pathophysiology pre-clinical drug evaluation iron-sulphur mitochondria 

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Copyright information

© Steinkopff-Verlag 2009

Authors and Affiliations

  1. 1.IGBMC Inserm, U596, CNRS, Université Louis Pasteur, UMR7104Collège de France, Chaire de génétique humaineIllkirchFrance

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