Clinical, biochemical and molecular genetic correlations in Friedreich's ataxia

Abstract

Friedreich's ataxia (FRDA) is an autosomal recessive disorder with a frequency of 1 in 50 000 live births. In 97% of patients it is caused by the abnormal expansion of a GAA repeat in intron 1 of the FRDA gene on chromosome 9, which encodes a 210 amino acid protein called frataxin. Frataxin is widely expressed and has been localized to mitochondria although its function is unknown. We have investigated mitochondrial function, mitochondrial DNA levels, aconitase activity and iron content in tissues from FRDA patients. There were significant reductions in the activities of complex I, complex II/III and aconitase in FRDA heart. Respiratory chain and aconitase activities were decreased although not significantly in skeletal muscle, but were normal in FRDA cerebellum and dorsal root ganglia, although there was a mild decrease in aconitase activity in the latter. Mitochondrial DNA levels were reduced in FRDA heart and skeletal muscle, although in skeletal muscle this was paralleled by a decline in citrate synthase activity. Increased iron deposition was seen in FRDA heart, liver and spleen in a pattern consistent with a mitochondrial location. The iron accumulation, mitochondrial respiratory chain and aconitase dysfunction and mitochondrial DNA depletion in FRDA heart samples largely paralleled those in the yeast YFH1 knockout model, suggesting that frataxin may be involved in mitochondrial iron regulation or iron sulphur centre synthesis. However, the severe deficiency in aconitase activity also suggests that oxidant stress may induce a self-amplifying cycle of oxidative damage and mitochondrial dysfunction, which may contribute to cellular toxicity.

Friedreich Ataxia Mouse Models with Progressive Cerebellar and Sensory Ataxia Reveal Autophagic Neurodegeneration in Dorsal Root Ganglia

“…i, The large-diameter axons are degenerating in the absence of myelin alteration. Scale bars, 2.5 m. ab, Autophagic body; go, Golgi; L, lysosome; lf, lipofuscin; mb, membrane; m, mitochondria; nu, nucleus; r, polyribosome; rer, rough endoplasmic reticulum; v, vacuole. disease, with rare deposits seen in the dorsal horn, brain stem, cerebellar granular layer, and cortex (data not shown), confirming that this is a late event in the pathological process (H. Seznec, D. Simon, L. Monassier, P. Criqui-Filipe, A. Gansmuller, P. Rustin, M. Koenig, and H. Puccio, unpublished observations), and is reminiscent of the situation in FRDA patients (Lamarche et al, 1993;Waldvogel et al, 1999;Bradley et al, 2000).…”

“…In FRDA patients, iron deposits have been observed in heart (Lamarche et al, 1993). Moreover, deficiencies of ISC-containing respiratory chain complexes I-III and aconitases have been demonstrated in heart biopsies (Rotig et al, 1997) and in the DRG (aconitases) (Bradley et al, 2000). Finally, there is evidence of increased oxidative stress in patients with elevated urine 8-hydroxy-2Ј-deoxyguanosine and serum malondialdehyde levels (indicative of DNA damage and lipid peroxidation, respectively) (Emond et al, 2000;Schulz et al, 2000) and an impaired response to oxidative challenge in patients' fibroblasts (Chantrel-Groussard et al, 2001).…”

Mitochondrial dysfunction in human pathologies

“…Aconitase deficiency is suggestive that oxidative stress may induce a self-amplifying cycle of oxidative damage associated with mitochondrial dysfunction, which may also contribute to cellular toxicity and degeneration (223). There are also evidences of an impairment in vivo of glutathione homeostasis and antioxidant enzymes in patients with Friedreich's ataxia, suggesting a relevant role of free radical cytotoxicity in the pathophysiology of the disease.…”

Cells Lacking Pfh1, a Fission Yeast Homolog of Mammalian Frataxin Protein, Display Constitutive Activation of the Iron Starvation Response

“…Thus, the cardiac tissues from patients with Friedreich ataxia contain iron deposits, are deficient in respiratory complexes I-III and aconitase activities, and have reduced mitochondrial DNA (6,7). The finding of iron accumulation in the hearts of both patients and mouse models (6,8,9) suggests that excess free iron is involved in the production of reactive oxygen species and is responsible for the oxidative damage to iron-sulfur clusters (ISCs) 3 and loss of mitochondrial DNA (10).…”