Increased levels of plasma malondialdehyde in Friedreich ataxia

Emond, Monique; Lepage, Guy; Vanasse, Michel; Pandolfo, Massimo

doi:10.1212/wnl.55.11.1752

Cited by 163 publications

(100 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…to produce the toxic hydroxyl radical (OH ⅐ ), and iron-mediated oxidative stress has been hypothesized to underlie the pathophysiology of the disease. Increased levels of oxidative stress markers such as plasma malondialdehyde and urine 8-hydroxy-2-deoxyguanosine have been found in patients with FRDA, and improvement of cardiac and skeletal muscle bioenergetics has been observed after antioxidant treatment (11)(12)(13)(14)(15). Moreover, we found an impairment in vivo of the antioxidant enzymes superoxide dismutase and glutathione peroxidase and decreased levels of free glutathione in the blood of patients with FRDA (16,17).…”

mentioning

confidence: 60%

Actin Glutathionylation Increases in Fibroblasts of Patients with Friedreich's Ataxia

Pastore

Tozzi

Gaeta

et al. 2003

Journal of Biological Chemistry

153

151

View full text Add to dashboard Cite

Increasing evidence suggests that iron-mediated oxidative stress might underlie the development of neurodegeneration in Friedreich's ataxia (FRDA), an autosomal recessive ataxia caused by decreased expression of frataxin, a protein implicated in iron metabolism. In this study, we demonstrate that, in fibroblasts of patients with FRDA, the cellular redox equilibrium is shifted toward more protein-bound glutathione. Furthermore, we found that actin is glutathionylated, probably as a result of the accumulation of reactive oxygen species, generated by iron overload in the disease. Indeed, highpressure liquid chromatography analysis of control fibroblasts in vivo treated with FeSO 4 showed a significant increase in the protein-bound/free GSH ratio, and Western blot analysis indicated a relevant rise in glutathionylation. Actin glutathionylation contributes to impaired microfilament organization in FRDA fibroblasts. Rhodamine phalloidin staining revealed a disarray of actin filaments and a reduced signal of F-actin fluorescence. The same hematoxylin/eosin-stained cells showed abnormalities in size and shape. When we treated FRDA fibroblasts with reduced glutathione, we obtained a complete rescue of cytoskeletal abnormalities and cell viability. Thus, we conclude that oxidative stress may induce actin glutathionylation and impairment of cytoskeletal functions in FRDA fibroblasts.Oxidative stress has been proposed to underlie neurodegeneration in Friedreich's ataxia (FRDA), 1 the most common of the hereditary ataxias, caused by severely reduced levels of frataxin, a protein implicated in iron metabolism. FRDA is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy, and increased incidence of diabetes. Most patients (95%) are homozygous for the hyperexpansion of a GAA repeat sequence in the first intron of the frataxin gene; a few are heterozygous for a GAA expansion and a point mutation (1-3). Data from yeast suggest that frataxin deficiency results in iron accumulation within mitochondria and increased sensitivity to oxidative stress (4, 5). Mouse models for FRDA exhibit cardiomyopathy, sensory nerve defects, and Fe-S enzyme deficiency followed by intramitochondrial iron deposits (6). Patients with FRDA have iron deposits in the heart, increased mitochondrial iron in fibroblasts, and greater sensitivity to oxidative stress by pro-oxidants such as FeCl 3 and hydrogen peroxide (3,7,8). Furthermore, a defective mitochondrial respiratory chain has been found in FRDA tissues, in association with iron accumulation and moderate decreases in mtDNA levels (9, 10).Iron is a crucial reagent in the Fenton reaction, as it can react with mitochondrially generated superoxide anion (O 2 . ) to produce the toxic hydroxyl radical (OH ⅐ ), and iron-mediated oxidative stress has been hypothesized to underlie the pathophysiology of the disease. Increased levels of oxidative stress markers such as plasma malondialdehyde and urine 8-hydroxy-2-deoxyguanosine have been found in patients with F...

show abstract

mentioning

confidence: 60%

Actin Glutathionylation Increases in Fibroblasts of Patients with Friedreich's Ataxia

Pastore

Tozzi

Gaeta

et al. 2003

Journal of Biological Chemistry

153

151

View full text Add to dashboard Cite

show abstract

“…Frataxin has been shown primarily to direct synthesis of iron-sulphur clusters within mitochondria (5). Secondarily, lack of frataxin causes increased levels of ROS both in vivo (7,8) and in vitro (11,12). β Cells are exceptionally sensitive to ROS (35).…”

Section: Discussionmentioning

confidence: 99%

“…A wide body of evidence suggests a role for frataxin in promoting cellular defense against reactive oxygen species (ROS): clinical data demonstrate increased oxidative stress in patients with FA (7,8). Findings from animal models suggest that, while the nonconditional knockout is embryonically lethal (9), the tissue-specific targeted disruption of the frataxin gene in heart or neuronal tissues causes depletion of iron-sulfur clusters, presumably accompanied by ROS formation (10).…”

Section: Introductionmentioning

confidence: 99%

Frataxin deficiency in pancreatic islets causes diabetes due to loss of β cell mass

Ristow¹,

Mulder²,

Pomplun³

et al. 2003

J. Clin. Invest.

View full text Add to dashboard Cite

Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing β cells. We have disrupted expression of the mitochondrial protein frataxin selectively in pancreatic β cells. Mice were born healthy but subsequently developed impaired glucose tolerance progressing to overt diabetes mellitus. These observations were explained by impairment of insulin secretion due to a loss of β cell mass in knockout animals. This phenotype was preceded by elevated levels of reactive oxygen species in knockout islets, an increased frequency of apoptosis, and a decreased number of proliferating β cells. Hence, disruption of the frataxin gene in pancreatic β cells causes diabetes following cellular growth arrest and apoptosis, paralleled by an increase in reactive oxygen species in islets. These observations might provide insight into the deterioration of β cell function observed in different subtypes of diabetes in humans

show abstract

“…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). We have recently generated two conditional knock-out models for FRDA, a cardiac and a neuronal-cardiac model, which reproduce important pathophysiological features of the human disease .…”

Section: Introductionmentioning

confidence: 99%

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

Simon¹,

Seznec²,

Gansmüller³

et al. 2004

J. Neurosci.

180

139

View full text Add to dashboard Cite

Friedreich ataxia (FRDA), the most common recessive ataxia, is characterized by degeneration of the large sensory neurons of the spinal cord and cardiomyopathy. It is caused by severely reduced levels of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biosynthesis. Through a spatiotemporally controlled conditional gene-targeting approach, we have generated two mouse models for FRDA that specifically develop progressive mixed cerebellar and sensory ataxia, the most prominent neurological features of FRDA. Histological studies showed both spinal cord and dorsal root ganglia (DRG) anomalies with absence of motor neuropathy, a hallmark of the human disease. In addition, one line revealed a cerebellar granule cell loss, whereas both lines had Purkinje cell arborization defects. These lines represent the first FRDA models with a slowly progressive neurological degeneration. We identified an autophagic process as the causative pathological mechanism in the DRG, leading to removal of mitochondrial debris and apparition of lipofuscin deposits. These mice therefore represent excellent models for FRDA to unravel the pathological cascade and to test compounds that interfere with the degenerative process.

show abstract

Increased levels of plasma malondialdehyde in Friedreich ataxia

Cited by 163 publications

References 7 publications

Actin Glutathionylation Increases in Fibroblasts of Patients with Friedreich's Ataxia

Actin Glutathionylation Increases in Fibroblasts of Patients with Friedreich's Ataxia

Frataxin deficiency in pancreatic islets causes diabetes due to loss of β cell mass

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

Contact Info

Product

Resources

About