Abstract
Friedreich ataxia (FRDA), the most common recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts and cardiomyopathy. It is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biosynthesis. Mouse models have been important tools in dissecting the steps of pathogenesis in FRDA. Furthermore, animal models that reproduce some of the key events in a pathology are essential for the development of effective therapies, both pharmacological and gene therapy approaches. This chapter presents an overview of the current mouse models that have been developed for FRDA.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Babcock M, de Silva D, Oaks R, Davis-Kaplan S, Jiralerspong S, Montermini L, Pandolfo M, Kaplan J (1997) Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science 276:1709–1712
Brunk UT, Terman A (2002) Lipofuscin: mechanisms of age-related accumulation and influence on cell function. Free Radic Biol Med 33:611–619
Bulteau AL, O’Neill HA, Kennedy MC, Ikeda-Saito M, Isaya G, Szweda LI (2004) Frataxin acts as an iron chaperone protein to modulate mitochondrial aconitase activity. Science 305:242–245
Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A et al (1996) Friedreich’s ataxia: autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271:1423–1427
Chantrel-Groussard K, Geromel V, Puccio H, Koenig M, Munnich A, Rotig A, Rustin P (2001) Disabled early recruitment of antioxidant defenses in Friedreich’s ataxia. Hum Mol Genet 10:2061–2067
Cossee M, Schmitt M, Campuzano V, Reutenauer L, Moutou C, Mandel JL, Koenig M (1997) Evolution of the Friedreich’s ataxia trinucleotide repeat expansion: founder effect and premutations. Proc Natl Acad Sci U S A 94:7452–7457
Cossee M, Puccio H, Gansmuller A, Koutnikova H, Dierich A, LeMeur M, Fischbeck K, Dolle P, Koenig M (2000) Inactivation of the Friedreich ataxia mouse gene leads to early embryonic lethality without iron accumulation. Hum Mol Genet 9:1219–1226
Gerber J, Muhlenhoff U, Lill R (2003) An interaction between frataxin and Isu1/Nfs1 that is crucial for Fe/S cluster synthesis on Isu1. EMBO Rep 4:906–911
Gillis JC, Benefield P, McTavish D (1994) Idebenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in age-related cognitive disorders. Drugs Aging 5:133–152
Harding AE (1981) Friedreich’s ataxia: a clinical and genetic study of 90 families with an analysis of early diagnostic criteria and intrafamilial clustering of clinical features. Brain 104:589–620
Huynen MA, Snel B, Bork P, Gibson TJ (2001) The phylogenetic distribution of frataxin indicates a role in iron-sulfur cluster protein assembly. Hum Mol Genet 10:2463–2468
Lamarche JB, Cote M, Lemieux B (1980) The cardiomyopathy of Friedreich’s ataxia morphological observations in 3 cases. Can J Neurol Sci 7:389–396
Lamarche J, Luneau C, Lemieux B (1982) Ultrastructural observations on spinal ganglion biopsy in Friedreich’s ataxia: a preliminary report. Can J Neurol Sci 9:137–139
Larnaout A, Belal S, Zouari M, Fki M, Ben Hamida C, Goebel HH, Ben Hamida M, Hentati F (1997) Friedreich’s ataxia with isolated vitamin E deficiency: a neuropathological study of a Tunisian patient. Acta Neuropathol (Berl) 93:633–637
Lemasters JJ, L Nieminen A, Qian T, Trost LC, Elmore SP, Nishimura Y, Crowe RA, Cascio WE, Bradham CA, Brenner DA, Herman B (1998) The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta 1366:177–196
Miranda CJ, Santos MM, Ohshima K, Smith J, Li L, Bunting M, Cossee M, Koenig M, Sequeiros J, Kaplan J, Pandolfo M (2002) Frataxin knockin mouse. FEBS Lett 512:291–297
Mordente A, Martorana GE, Minotti G, Giardina B (1998) Antioxidant properties of 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone (idebenone) Chem Res Toxicol 11:54–63
Muhlenhoff U, Richhardt N, Ristow M, Kispal G, Lill R (2002) The yeast frataxin homolog Yfh1p plays a specific role in the maturation of cellular Fe/S proteins. Hum Mol Genet 11:2025–2036
Pandolfo M (1998) Molecular genetics and pathogenesis of Friedreich ataxia. Neuromuscul Disord 8:409–415
Puccio H, Simon D, Cossee M, Criqui-Filipe P, Tiziano F, Melki J, Hindelang C, Matyas R, Rustin P, Koenig M (2001) Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits. Nat Genet 27:181–186
Reggiori F, Klionsky DJ (2002) Autophagy in the eukaryotic cell. Eukaryot Cell 1:11–21
Ristow M, Mulder H, Pomplun D, Schulz TJ, Muller-Schmehl K, Krause A, Fex M, Puccio H, Muller J, Isken F, Spranger J, Muller-Wieland D, Magnuson MA, Mohlig M, Koenig M Pfeiffer AF (2003) Frataxin deficiency in pancreatic islets causes diabetes due to loss of beta cell mass. J Clin Invest 112:527–534
Rotig A, de Lonlay P, Chretien D, Foury F, Koenig M, Sidi D, Munnich A, Rustin P (1997) Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet 17:215–217
Rustin P (2003) The use of antioxidants in Friedreich’s ataxia treatment. Expert Opin Investig Drugs 12:569–575
Santos MM, Ohshima K, Pandolfo M (2001) Frataxin deficiency enhances apoptosis in cells differentiating into neuroectoderm. Hum Mol Genet 10:1935–1944
Seznec H, Simon D, Monassier L, Criqui-Filipe P, Gansmuller A, Rustin P, Koenig M, Puccio H (2004) Idebenone delays the onset of cardiac functional alteration without correction of Fe-S enzymes deficit in a mouse model for Friedreich ataxia. Hum Mol Genet 13:1017–1024
Seznec H, Simon D, Bouton C, Reutenauer L, Hertzog A, Golik P, Procaccio V, Patel M, Drapier JC, Koenig M, Puccio H (2005) Friedreich ataxia: the oxidative stress paradox. Hum Mol Genet 14:463–474
Simon D, Seznec H, Gansmuller A, Carelle N, Weber P, Metzger D, Rustin P, Koenig M, Puccio H (2004) Friedreich ataxia mouse models with progressive cerebellar and sensory ataxia reveal autophagic neurodegeneration in dorsal root ganglia. J Neurosci 24:1987–1995
Weber P, Metzger D, Chambon P (2001) Temporally controlled targeted somatic mutagenesis in the mouse brain. Eur J Neurosci 14:1777–1783
Wilson RB, Roof DM (1997) Respiratory deficiency due to loss of mitochondrial DNA in yeast lacking the frataxin homologue. Nat Genet 16:352–357
Wong A, Yang J, Cavadini P, Gellera C, Lonnerdal B, Taroni F, Cortopassi G (1999) The Friedreich’s ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis. Hum Mol Genet 8:425–430
Xue L, Fletcher GC, Tolkovsky AM (1999) Autophagy is activated by apoptotic signalling in sympathetic neurons: an alternative mechanism of death execution. Mol Cell Neurosci 14:180–198
Yoon T, Cowan JA (2003) Iron-sulfur cluster biosynthesis. Characterization of frataxin as an iron donor for assembly of [2Fe-2S] clusters in ISU-type proteins. J Am Chem Soc 125:6078–6084
Yoon T, Cowan JA (2004) Frataxin-mediated iron delivery to Ferrochelatase in the final step of Heme biosynthesis. J Biol Chem 27:27
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2007 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Puccio, H. (2007). Conditional Mouse Models for Friedreich Ataxia, a Neurodegenerative Disorder Associating Cardiomyopathy. In: Feil, R., Metzger, D. (eds) Conditional Mutagenesis: An Approach to Disease Models. Handbook of Experimental Pharmacology, vol 178. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-35109-2_15
Download citation
DOI: https://doi.org/10.1007/978-3-540-35109-2_15
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-35108-5
Online ISBN: 978-3-540-35109-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)