Open Access Research article

Limitations in a frataxin knockdown cell model for Friedreich ataxia in a high-throughput drug screen

Nadège Calmels1, Hervé Seznec15, Pascal Villa2, Laurence Reutenauer1, Marcel Hibert23, Jacques Haiech23, Pierre Rustin4, Michel Koenig1 and Hélène Puccio1*

Author Affiliations

1 IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), CNRS/INSERM/Université Louis Pasteur, 67404 Illkirch cedex, France

2 IFR 85/PCBIS (Plateforme de Chimie Biologique Intégrative de Strasbourg), ESBS Pôle API, 67401 Illkirch, France

3 UMR7175/CNRS/Université Louis Pasteur, 67404 Illkirch cedex, France

4 INSERM U676, Hôpital Robert Debré, 75019 Paris, France

5 Interface Physique Biologie, Centre d'Etudes Nucléaires de Bordeaux-Gradignan, CNRS/IN2P3-UMR5797, BP120 - 33175 Gradignan, France

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BMC Neurology 2009, 9:46  doi:10.1186/1471-2377-9-46

Published: 24 August 2009



Pharmacological high-throughput screening (HTS) represents a powerful strategy for drug discovery in genetic diseases, particularly when the full spectrum of pathological dysfunctions remains unclear, such as in Friedreich ataxia (FRDA). FRDA, the most common recessive ataxia, results from a generalized deficiency of mitochondrial and cytosolic iron-sulfur cluster (ISC) proteins activity, due to a partial loss of frataxin function, a mitochondrial protein proposed to function as an iron-chaperone for ISC biosynthesis. In the absence of measurable catalytic function for frataxin, a cell-based assay is required for HTS assay.


Using a targeted ribozyme strategy in murine fibroblasts, we have developed a cellular model with strongly reduced levels of frataxin. We have used this model to screen the Prestwick Chemical Library, a collection of one thousand off-patent drugs, for potential molecules for FRDA.


The frataxin deficient cell lines exhibit a proliferation defect, associated with an ISC enzyme deficit. Using the growth defect as end-point criteria, we screened the Prestwick Chemical Library. However no molecule presented a significant and reproducible effect on the proliferation rate of frataxin deficient cells. Moreover over numerous passages, the antisense ribozyme fibroblast cell lines revealed an increase in frataxin residual level associated with the normalization of ISC enzyme activities. However, the ribozyme cell lines and FRDA patient cells presented an increase in Mthfd2 transcript, a mitochondrial enzyme that was previously shown to be upregulated at very early stages of the pathogenesis in the cardiac mouse model.


Although no active hit has been identified, the present study demonstrates the feasibility of using a cell-based approach to HTS for FRDA. Furthermore, it highlights the difficulty in the development of a stable frataxin-deficient cell model, an essential condition for productive HTS in the future.