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

Simon, Delphine; Seznec, Hervé; Gansmüller, Anne; Carelle, Nadège; Weber, Philipp; Metzger, Daniel; Rustin, Pierre; Kœnig, M.; Puccio, Hélène

doi:10.1523/jneurosci.4549-03.2004

Cited by 177 publications

(151 citation statements)

References 50 publications

(48 reference statements)

Supporting

Mentioning

139

Contrasting

Unclassified

Order By: Relevance

“…[21][22][23] In FA, the evidence of iron accumulation in mitochondria 5,8,9 was supported by studies indicating early iron accumulation in the cerebellum of patients (particularly the dentate nuclei). 10,15 However, the pathologic role of iron as a causative or exacerbating factor in FA 5,40 and in other neurologic disorders [11][12][13]16 has remained a matter of debate. Similarly controversial is the use of iron chelators for treating FA and other neurologic conditions.…”

Section: Discussionmentioning

confidence: 99%

Selective iron chelation in Friedreich ataxia: biologic and clinical implications

Boddaert

Sang

Rötig

et al. 2007

Blood

378

317

View full text Add to dashboard Cite

Genetic disorders of iron metabolism and chronic inflammation often evoke local iron accumulation. In Friedreich ataxia, decreased iron-sulphur cluster and heme formation leads to mitochondrial iron accumulation and ensuing oxidative damage that primarily affects sensory neurons, the myocardium, and endocrine glands. We assessed the possibility of reducing brain iron accumulation in Friedreich ataxia patients with a membranepermeant chelator capable of shuttling chelated iron from cells to transferrin, using regimens suitable for patients with no systemic iron overload. Brain magnetic resonance imaging (MRI) of Friedreich ataxia patients compared with agematched controls revealed smaller and irregularly shaped dentate nuclei with significantly (P < .027) higher H-relaxation rates R2*, indicating regional iron accumulation. A 6-month treatment with 20 to 30 mg/kg/d deferiprone of 9 adolescent patients with no overt cardiomyopathy reduced R2* from 18.3 s ؊1 (؎ 1.6 s ؊1 ) to 15.7 s ؊1 (؎ 0.7 s ؊1 ; P < .002), specifically in dentate nuclei and proportionally to the initial R2* (r ‫؍‬ 0.90). Chelator treatment caused no apparent hematologic or neurologic side effects while reducing neu- IntroductionTissue iron overload and ensuing organ damage have generally been identified with transfusional hemosiderosis and genetic hemochromatosis. 1 Liver, heart, and endocrine glands are among the most affected organs in these forms of systemic iron overload. 1 The source of tissue iron overload has been traced to plasma iron originating from enteric hyperabsorption of the metal and/or enhanced red cell destruction. The labile forms of plasma iron (LPI) that appear as transferrin become saturated, permeate into particular cell types by unregulated mechanisms, and cause labile iron pools to raise and challenge cellular antioxidant capacities. 2 However, in chronic inflammation 3 and in various genetic disorders, 4 iron accumulates in particular cell types attaining toxic levels, even in the absence of circulating LPI and often even in iron-deficient plasma. In Friedreich ataxia (FA), an expansion of a GAA repeat in the first intron of the nuclear encoded frataxin gene 5,6 results in underexpression of a mitochondrial protein involved in the assembly of iron-sulphur cluster proteins (ISPs) and/or in protecting mitochondria from iron-mediated oxidative damage. 7 The defective ISP formation that causes a combined aconitase and respiratory chain deficiency (complex I-III) leads in turn to mitochondrial accumulation of labile iron 8,9 and ensuing oxidative damage in brain, heart, and endocrine glands. However, the pathophysiologic role of mitochondrial iron accumulation in oxidative damage found in FA 5,9 and other neurologic disorders [10][11][12][13] has not been resolved.In analogy to transfusional iron overload, histopathologic and magnetic resonance imaging (MRI) studies of FA patients have shown that iron accumulates not only in the heart but also in the spinocerebellar tracts (dentate nuclei) and spinal cord. 10 Those and othe...

show abstract

Section: Discussionmentioning

confidence: 99%

Selective iron chelation in Friedreich ataxia: biologic and clinical implications

Boddaert

Sang

Rötig

et al. 2007

Blood

378

317

View full text Add to dashboard Cite

show abstract

“…This was carried out as described in the literature. [23][24][25] Briefly, animals were gently placed on the grid of the dynamometer and pulled by their tails in the opposite direction. The maximum grip strength exerted by the rat before losing grip was recorded.…”

Section: Animalsmentioning

confidence: 99%

Anti-fatigue Effect of Ginsenoside Rb1 on Postoperative Fatigue Syndrome Induced by Major Small Intestinal Resection in Rat

Tan

Zhou

et al. 2013

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Ginsenoside Rb1 (GRb1), one of the principle active ingredients of Panax ginseng, exerts multiple pharmacological activities to fight fatigue. In the present study, we investigate the anti-fatigue effect of GRb1 on postoperative fatigue syndrome (POFS) in a rat model induced by major small intestinal resection. GRb1 (10 mg/kg) was administrated intraperitoneally once daily for 1, 3, 7, and 10 d from the operation day. Antifatigue effect was assessed by grasping test and biochemical parameters in blood or skeletal muscle were determined by autoanalyzer or commercially available kits. Transmission electron microscope was applied to observe the ultra microstructure of skeletal muscles. The results revealed that GRb1 significantly enhanced rat maximum grip strength with POFS. Similarly, negative alterations in biochemical parameters (lactic acid, hepatic glycogen, muscle glycogen and malondialdehyde) of POFS rats were improved by GRb1. In addition, GRb1 also increased the activity of lactate dehydrogenase and superoxide dismutase in POFS. No significant differences of levels of blood urea nitrogen and ultra microstructure of skeletal muscles were found between the POFS and GRb1 treatment rats. The potent anti-fatigue effect of GRb1 on POFS might be achieved through improvement of energy metabolism and suppression of skeletal muscle oxidative stress.Key words ginsenoside Rb1; postoperative fatigue syndrome; energy metabolism; oxidative stress; animal experiment Ginseng, the dried root of Panax ginseng C. A. MEYER (Araliaceae), has been used as a tonic to treat various disorders in Chinese traditional medicine. It is considered the king of herbs since the earliest Chinese pharmaceutical monograph "Shen Nong Ben Cao Jing." 1) Currently, ginseng is used worldwide as a popular herbal medicine, especially in China, Korea and Japan. Ginsenosides are thought to be the main active ingredients of ginseng with multiple pharmacological activities including anti-aging, anti-carcinogenic, anti-oxidation, antiinflammation, and anti-fatigue.2-6) Modern science has identified more than 50 kinds of ginsenosides. Ginsenoside Rb1 (GRb1), one of the ginsenosides, belongs to the protopanaxadiol group of steroidal saponins. Accumulating evidence indicates that GRb1 exerts a protective effect against stress in various conditions. [7][8][9] Currently, one of the major tasks of surgery is to enhance the recovery after operation. Postoperative fatigue syndrome (POFS) is a common complication after surgery, especially major abdominal and cardiac procedures. 10) For affected patients, POFS manifests itself as a feeling of malaise, lethargy, loss of energy, concentration difficulties and debilitating fatigue. It can persist for up to one month after abdominal operations and gradually resolves in as long as 3 months after uncomplicated gastrointestinal surgery.11-13) Patients who suffer from POFS have a prolonged recovery to normal daily life. In addition, POFS increases health-service costs, burdens patients themselves, their families, hospitals...

show abstract

“…Several model systems have been developed to understand the disease. Both decreased expression of frataxin protein (224), and selective inactivation in neuronal tissues are associated with neurological symptoms, mitochondrial iron-sulfur cluster-containing enzyme deficiencies and time-dependent mitochondrial iron accumulation (225).…”

Section: Friedreich Ataxia (Frda)mentioning

confidence: 99%

Mitochondrial dysfunction in human pathologies

Monsalve¹

2007

Front Biosci

View full text Add to dashboard Cite

The integrity of mitochondrial function is fundamental to cell life. The cell demands for mitochondria and their complex integration into cell biology, extends far beyond the provision of ATP. It follows that disturbances of mitochondrial function lead to disruption of cell function, expressed as disease or even death. Mitochondria are major producers of free radical species and also possibly of nitric oxide, and are, at the same time, major targets for oxidative damage. In this review we consider recent developments in our knowledge of how the mitochondrial production of reactive oxygen species (ROS) plays a critical role in several major human pathologies. We will also consider recent advances in our understanding of the molecular mechanisms involved in mitochondrial ROS detoxification.

show abstract

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

Cited by 177 publications

References 50 publications

Selective iron chelation in Friedreich ataxia: biologic and clinical implications

Selective iron chelation in Friedreich ataxia: biologic and clinical implications

Anti-fatigue Effect of Ginsenoside Rb1 on Postoperative Fatigue Syndrome Induced by Major Small Intestinal Resection in Rat

Mitochondrial dysfunction in human pathologies

Contact Info

Product

Resources

About