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Molecular and biochemical pathogenesis of friedreich's ataxia: search for treatments.


The final goal of this proposal is to identify treatments and outcome measures for multicenter treatment trials for Friedreich's ataxia (FRDA), the most frequent cause of inherited ataxia and which is of exclusive European/Caucasian origin. We will develop mouse and cell culture models of FRDA, which will be used to identify mechanisms by which reduced expression of frataxin, the defective mitochondrial protein, or expression of mutated frataxin causes cell death. Possible treatments interfering with the proposed pathogenesis will be tested in the in vitro and in vivo models. Giving its slow progression and the phenotypic variability, FRDA may be a difficult disease to study for therapeutic intervention. Therefore, we will try to identify biochemical markers of oxidative stress and mitochondrial dysfunction, which in later therapeutic trials may be followed as primary outcome measures for the effectiveness of a treatment.
D 1.2 and D 1.3 Biochemistry of DYFH1 yeast mutants and genes interacting with YFH1. This work has identified the metabolic pathway of yeast frataxin : the mitochondrial iron-sulfur (Fe-S) cluster biosynthesis machinery (Duby et al. 2002). It has identified the functional and physical partner of yeast frataxin: Isu1p, the protein that serves as a scaffold for 2Fe-2S cluster assembly, and it has provided biological support to the in vitro view that frataxin may be an iron donor to Isup (Ramazzotti et al. submitted). D 2.2 and D 2.3 Conditional and inducible frataxin knock-out mice. Four transgenic mouse lines that recapitulate several aspects of FRDA pathology were constructed and characterized : a model with cardiomyopathy (Puccio et al. 2001), two models with progressive dorsal root ganglia, posterior columns and cerebellar degeneration (Simon et al., in preparation), and a severe model with both cardiac and neuronal pathology (Puccio et al. 2001). No other FRDA mouse model with significant pathology are currently available D 3.1 D 3.2 and D 3.3 Cell lines with frataxin deficiency. Mouse fibroblasts with complete frataxin depletion (Seznec et al., in preparation) and neuroblastoma and primary cerebellar granule neurons depleted in frataxin by adenovirus mediated antisense RNA (Gerhardt et al., in preparation) were not viable in culture, indicating an essential role for frataxin in dividing cells.

When stressed with various oxidative compounds (oligomycine, BSO...) patient fibroblasts, which express residual amounts of frataxin, revealed differential cell death compared to control fibroblasts and were used for drug screening (Rötig et al. 2001; Jauslin et al.2002). D 4.1 Mitochondrial function of cell and animal models. The mouse models allowed to demonstrate that the deficiency of the Fe-S proteins precedes iron accumulation and hence iron-induced oxidative stress (Puccio et al. 2001 and Seznec et al. submitted). D 5.1 D 6.1 and D 6.2 Identification of cell death mechanisms and behavioral and pathological abnormalities of the animal models The mouse and yeast models allowed to demonstrate that mitochondrial iron accummulation is not the primary event of the disease, making iron-chelator therapeutic strategies obsolete (Puccio et al. 2001 and Seznec et al. submitted). Histological studies of the progressive neurological mouse models revealed that the formation of vacuoles in the large sensory neurons of the dorsal root ganglia is a specific hallmark of the frataxin deficient neurons. We identified an autophagic process as the causative pathological mechanism in the DRG, leading to removal of mitochondrial debris and lipofuscin deposits, most likely corresponding to oxidized catabolic products (Simon et al., in press). D 7.1 Identification of biochemical markers for the progression of FRDA. We studied surrogate markers of oxidative stress in vivo to test its involvment in the pathogenesis of Friedreich's ataxia. Urine levels of 8 oxoguanine, a product of DNA oxidation by hydroxyl radicals, were shown to be an effective marker of oxidative stress in FRDA pathology (Schulz et al., 2000). D 7.2 and D8.3 Identification of promising drugs in cell culture and transgenic animal models for the treatment of FRDA and preclinical testing of drug compounds. Both patient studies in an open trial and double blind assays on the mouse with FRDA cardiomyopathy demonstrated that idebenone, a lipophylic antioxidant is cardioprotective (Hausse et al. 2002; Rustin et al. 2002; Rustin et al. in press [2004]; Seznec et al. submitted).

These results have prompted the use of idebenone in a phase I clinical trial, with doses adapted to our effective therapeutic range (ie increased). On the contrary, the mouse model with cardiomyopathy revealed that a soluble antioxidant, tetrakis-(4-benzoic acid) porphyrin (MnTBAP), a synthetic superoxide dismutase, is not effective and that low and high iron diet have no effect on disease outcome, excluding iron chelators as a therapy for FRDA (Seznec et al., in preparation). By using the patients' fibroblast model, we have identified several classes of potentially bioactive molecules which could prevent the FRDA-cell death caused by BSO. These include known antioxidant such as idebenone and vitamine E, but also novel molecules such as selenium and small molecule glutathione peroxidase mimetics (Jauslin et al. 2002). We also found that antioxidant mixtures have synergistic effect such as for equimolar mixtures of idebenone/vitamin E, and also with novel synthetic molecules consisting of the active moieties from both antioxidants (Jauslin et al. submitted). As an alternative approach, we compared idebenone to a mitochondrial-targeted version of idebenone (MitoQ) and found, that this was several hundred times more potent than the non targeted version (Jauslin et al. 2003). This is of relevance, since to date idebenone shows relatively low efficacy on the neurological symptoms of FRDA patients.


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