A cellular model for Friedrich ataxia and its application in drug discovery

Schoumacher, Fabrice, Jauslin, Matthias L., Wirth, Thomas ORCID: https://orcid.org/0000-0002-8990-0667 and Meier, Thomas 2002. A cellular model for Friedrich ataxia and its application in drug discovery. Neuromuscular Disorders 12 (7-8) , p. 774.

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Abstract

Friedrich ataxia (FRDA) is the most prevalent inherited ataxia. Reduced expression levels of Frataxin, a nuclear encoded mitochondrial protein leads to increased oxidative stress and continuous damage to iron/sulfur cluster proteins, among them several key elements of the mitochondrial respiratory chain. There is currently no cure for this disease, but idebenone, a short chain CoenzymeQ analog with antioxidant properties has shown promising results in a limited number of clinical studies. However, there is currently no cellular model available to conduct a rational search for therapeutically active drug candidates. For this purpose, we have developed such a model using primary cultures of fibroblasts from FRDA patients and control donors. We observed that FRDA cells are several orders of magnitude more sensitive than normal fibroblasts to inhibition of de novo glutathione synthesis. Using this discriminating, disease-relevant assay, we found that idebenone was able to rescue FRDA fibroblasts from cell death, thereby validating this cellular assay for drug screening purposes. We identified several classes of active molecules. Structural analysis revealed molecular features implicated in the activity. Moreover, these findings highlighted a novel disease pathway that hold the potential for pharmalogical intervention.

Item Type:	Article
Schools:	Chemistry
Subjects:	Q Science > QD Chemistry
Additional Information:	Abstracts: T.P.3.7
Publisher:	Elsevier
ISSN:	0960-8966
Last Modified:	18 Oct 2022 12:25
URI:	https://orca.cardiff.ac.uk/id/eprint/9764

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