GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology

ObjectiveFriedreich's ataxia is an incurable inherited neurological disease caused by frataxin deficiency. Here, we report the neuroreparative effects of myeloablative allogeneic bone marrow transplantation in a humanized murine model of the disease.MethodsMice received a transplant of fluorescently tagged sex‐mismatched bone marrow cells expressing wild‐type frataxin and were assessed at monthly intervals using a range of behavioral motor performance tests. At 6 months post‐transplant, mice were euthanized for protein and histological analysis. In an attempt to augment numbers of bone marrow–derived cells integrating within the nervous system and improve therapeutic efficacy, a subgroup of transplanted mice also received monthly subcutaneous infusions of the cytokines granulocyte‐colony stimulating factor and stem cell factor.ResultsTransplantation caused improvements in several indicators of motor coordination and locomotor activity. Elevations in frataxin levels and antioxidant defenses were detected. Abrogation of disease pathology throughout the nervous system was apparent, together with extensive integration of bone marrow–derived cells in areas of nervous tissue injury that contributed genetic material to mature neurons, satellite‐like cells, and myelinating Schwann cells by processes including cell fusion. Elevations in circulating bone marrow–derived cell numbers were detected after cytokine administration and were associated with increased frequencies of Purkinje cell fusion and bone marrow–derived dorsal root ganglion satellite‐like cells. Further improvements in motor coordination and activity were evident.InterpretationOur data provide proof of concept of gene replacement therapy, via allogeneic bone marrow transplantation, that reverses neurological features of Friedreich's ataxia with the potential for rapid clinical translation. Ann Neurol 2018;83:779–793

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“…These mice are frataxin‐deficient and develop progressive neurodegeneration and cardiac pathology 16, 21, 30…”

Section: Resultsmentioning

confidence: 99%

Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice

Kemp

Hares

Redondo

et al. 2018

Annals of Neurology

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“…Mice are frataxin‐deficient and develop progressive neurodegeneration and cardiac pathology 28, 29. Because of the phenotypic similarity between C57BL/6 and Y47R mice (Y47R mice carry the human FXN transgene with normal‐sized GAA repeats), C57BL/6 mice were used as healthy controls 29.…”

Section: Resultsmentioning

confidence: 99%

Cytokine therapy‐mediated neuroprotection in a Friedreich's ataxia mouse model

Kemp

Cerminara

Hares

et al. 2017

Annals of Neurology

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ObjectivesFriedreich's ataxia is a devastating neurological disease currently lacking any proven treatment. We studied the neuroprotective effects of the cytokines, granulocyte‐colony stimulating factor (G‐CSF) and stem cell factor (SCF) in a humanized murine model of Friedreich's ataxia.MethodsMice received monthly subcutaneous infusions of cytokines while also being assessed at monthly time points using an extensive range of behavioral motor performance tests. After 6 months of treatment, neurophysiological evaluation of both sensory and motor nerve conduction was performed. Subsequently, mice were sacrificed for messenger RNA, protein, and histological analysis of the dorsal root ganglia, spinal cord, and cerebellum.ResultsCytokine administration resulted in significant reversal of biochemical, neuropathological, neurophysiological, and behavioural deficits associated with Friedreich's ataxia. Both G‐CSF and SCF had pronounced effects on frataxin levels (the primary molecular defect in the pathogenesis of the disease) and a regulators of frataxin expression. Sustained improvements in motor coordination and locomotor activity were observed, even after onset of neurological symptoms. Treatment also restored the duration of sensory nerve compound potentials. Improvements in peripheral nerve conduction positively correlated with cytokine‐induced increases in frataxin expression, providing a link between increases in frataxin and neurophysiological function. Abrogation of disease‐related pathology was also evident, with reductions in inflammation/gliosis and increased neural stem cell numbers in areas of tissue injury.InterpretationThese experiments show that cytokines already clinically used in other conditions offer the prospect of a novel, rapidly translatable, disease‐modifying, and neuroprotective treatment for Friedreich's ataxia. Ann Neurol 2017;81:212–226

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“…The disease is characterized by progressive ataxia of all limbs, skeletal and cardiac muscle myopathy, skeletal deformities, impaired glucose tolerance or diabetes mellitus, sensorineural deafness, and optic neuropathy [47]. The molecular abnormality in more than 97% of patients is GAA trinucleotide repeat expansion in intron 1 of the FXN gene [48]. Normal alleles of the FXN gene have 5 to 30 GAA repeat expansions; however, disease alleles have from 70 to more than 1,000 GAA triplets.…”

Section: Friedreich Ataxiamentioning

confidence: 99%

Iron transport: From enterocyte to mitochondria

Özbek¹

2010

Turk J Hematol

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Transport of iron to tissues is of vital importance. Remarkable advances have been made concerning the mechanisms involving iron metabolism after its absorption. Studies assessing cellular and mitochondrial iron metabolism have resulted in interesting findings. This review highlights the recent advances in the mechanisms involving transport and delivery of iron to tissues, cellular and mitochondrial iron metabolism, iron-related molecules, and mitochondrial disorders. (Turk J Hematol 2010; 27: 137-46) Key words: Iron, iron transport, mitochondria, mitochondrial iron Received: February 8, 2010 Accepted: April 6, 2010 ÖzetDemirin dokulara taşınması yaşamsal önem taşır. Demirin emiliminden sonraki metabolizmasıyla ilgili büyük ilerlemeler kaydedilmiştir. Selüler ve mitokondriyal demir metabolizmasıyla ilgili araştırmalar ilginç sonuçlar vermektedir. Bu derleme demirin dokulara taşınması, verilmesi, hücresel ve mitokondriyal demir metabolizması, demirle ilişkili moleküller ve mitokondriyal hastalıklarla ilgili yeni gelişme-leri vurgulamaktadır. (Turk J Hematol 2010; 27: 137-46) Anahtar kelimeler: Demir, demir taşınımı, mitokondri, mitokondriyal demir Geliş tarihi: 8 Şubat 2010 Kabul tarihi: 6 Nisan 2010A current theme in the field of hematology as well as in other disciplines is the molecular mechanisms concerning iron metabolism. Mechanisms involving absorption of iron by enterocytes has been reviewed elsewhere [1][2][3]. In this review, delivery of iron to tissues, mechanisms concerning cellular and mitochondrial iron metabolism, iron-related molecules, and mitochondrial disorders are presented (Table 1). Transport of iron in plasmaBinding to transferrin (Tf) is the first step in iron transport. Tf has high affinity for ferric iron; therefore, the oxidation of ferrous (Fe +2 ) to the ferric (Fe +3 ) form by hephaestin is an essential step for transport. Hephaestin is a ceruloplasmin homolog, and colocalizes with ferroportin at the basolateral membrane of enterocytes. The role of hephaestin in iron absorption was first shown in the sla (sex-

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GAA repeat expansion mutation mouse models of Friedreich ataxia exhibit oxidative stress leading to progressive neuronal and cardiac pathology

Cited by 214 publications

References 43 publications

Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice

Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice

Cytokine therapy‐mediated neuroprotection in a Friedreich's ataxia mouse model

Iron transport: From enterocyte to mitochondria

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