共查询到10条相似文献,搜索用时 171 毫秒
1.
Koeppen AH Michael SC Knutson MD Haile DJ Qian J Levi S Santambrogio P Garrick MD Lamarche JB 《Acta neuropathologica》2007,114(2):163-173
Frataxin deficiency in Friedreich’s ataxia (FRDA) causes cardiac, endocrine, and nervous system manifestations. Frataxin is
a mitochondrial protein, and adequate amounts are essential for cellular iron homeostasis. The main histological lesion in
the brain of FRDA patients is neuronal atrophy and a peculiar proliferation of synaptic terminals in the dentate nucleus termed
grumose degeneration. This cerebellar nucleus may be especially susceptible to FRDA because it contains abundant iron. We
examined total iron and selected iron-responsive proteins in the dentate nucleus of nine patients with FRDA and nine normal
controls by biochemical and microscopic techniques. Total iron (1.53 ± 0.53 μmol/g wet weight) and ferritin (206.9 ± 46.6
μg/g wet weight) in FRDA did not significantly differ from normal controls (iron: 1.78 ± 0.88 μmol/g; ferritin: 210.9 ± 9.0 μg/g)
but Western blots exhibited a shift to light ferritin subunits. Immunocytochemistry of the dentate nucleus revealed loss of
juxtaneuronal ferritin-containing oligodendroglia and prominent ferritin immunoreactivity in microglia and astrocytes. Mitochondrial
ferritin was not detectable by immunocytochemistry. Stains for the divalent metal transporter 1 confirmed neuronal loss while
endothelial cells reacting with antibodies to transferrin receptor 1 protein showed crowding of blood vessels due to collapse
of the normal neuropil. Regions of grumose degeneration were strongly reactive for ferroportin. Purkinje cell bodies, their
dendrites and axons, were also ferroportin-positive, and it is likely that grumose degeneration is the morphological manifestation
of mitochondrial iron dysmetabolism in the terminals of corticonuclear fibers. Neuronal loss in the dentate nucleus is the
likely result of trans-synaptic degeneration. 相似文献
2.
Arnulf H. Koeppen Jennifer A. Morral Ashley N. Davis Jiang Qian Simone V. Petrocine Mitchell D. Knutson Walter M. Gibson Matthew J. Cusack Danhong Li 《Acta neuropathologica》2009,118(6):763-776
Atrophy of dorsal root ganglia (DRG) and thinning of dorsal roots (DR) are hallmarks of Friedreich’s ataxia (FRDA). Many previous
authors also emphasized the selective vulnerability of larger neurons in DRG and thicker myelinated DR axons. This report
is based on a systematic reexamination of DRG, DR and ventral roots (VR) in 19 genetically confirmed cases of FRDA by immunocytochemistry
and single- and double-label immunofluorescence with antibodies to specific proteins of myelin, neurons and axons; S-100α
as a marker of satellite and Schwann cells; laminin; and the iron-responsive proteins ferritin, mitochondrial ferritin, and
ferroportin. Confocal images of axons and myelin allowed the quantitative analysis of fiber density and size, and the extent
of DR and VR myelination. A novel technology, high-definition X-ray fluorescence (HDXRF) of polyethylene glycol-embedded fixed
tissue, was used to “map” iron in DRG. Unfixed frozen tissue of DRG in three cases was available for the chemical assay of
total iron. Proliferation of S-100α-positive satellite cells accompanied neuronal destruction in DRG of all FRDA cases. Double-label
visualization of peripheral nerve myelin protein 22 and phosphorylated neurofilament protein confirmed the known loss of large
myelinated DR fibers, but quantitative fiber counts per unit area did not change. The ratio of myelinated to neurofilament-positive
fibers in DR rose significantly from 0.55 to 0.66. In VR of FRDA patients, fiber counts and degree of myelination did not
differ from normal. Pooled histograms of axonal perimeters disclosed a shift to thinner fibers in DR, but also a modest excess
of smaller axons in VR. Schwann cell cytoplasm in DR of FRDA was depleted while laminin reaction product remained prominent.
Numerous small axons clustered around fewer Schwann cells. Ferritin in normal DRG localized to satellite cells, and proliferation
of these cells in FRDA caused wide rims of reaction product about degenerating nerve cells. Mitochondrial ferritin was not
detectable. Ferroportin was present in the cytoplasm of normal satellite cells and neurons, and in large axons of DR and VR.
In FRDA, some DRG neurons lost their cytoplasmic ferroportin immunoreactivity, whereas the cytoplasm of satellite cells remained
ferroportin positive. Ferroportin in DR axons disappeared in parallel with atrophy of large fibers. HDXRF of DRG detected
regional and diffuse increases in iron fluorescence that matched ferritin expression in satellite cells. The observations
support the conclusions that satellite cells and DRG neurons are affected by iron dysmetabolism; and that regeneration and
inappropriate myelination of small axons in DR are characteristic of the disease. 相似文献
3.
Friedreich's ataxia (FRDA) is caused by point mutations or trinucleotide repeat expansions in both alleles of the gene encoding frataxin. Studies of frataxin homologues in lower eukaryotes suggest that mitochondrial iron accumulation may underlie the pathophysiology of FRDA. To evaluate the possible role of iron-chelation therapy for FRDA, we measured serum iron and ferritin concentration in 10 FRDA patients. The measurements were within normal limits, suggesting that iron-chelation therapy for FRDA may be problematic. 相似文献
4.
Abnormal iron homeostasis is increasingly thought to contribute to the pathogenesis of several neurodegenerative disorders. We have previously reported impaired iron homeostasis in a mouse model of spinal cord injury and in a mouse model of amyotrophic lateral sclerosis. Both these disorders are associated with CNS inflammation. However, what effect inflammation, and in particular, inflammatory cytokines have on iron homeostasis in CNS glia remains largely unknown. Here we report that the proinflammatory cytokine TNF-α, and the anti-inflammatory cytokine TGF-β1 affect iron homeostasis in astrocytes and microglia in distinct ways. Treatment of astrocytes in vitro with TNF-α induced the expression of the iron importer "divalent iron transporter 1" (DMT1) and suppressed the expression of the iron exporter ferroportin (FPN). However, TGF-β1 had no effect on DMT1 expression but increased the expression of FPN in astrocytes. In microglia, on the other hand, both cytokines caused induction of DMT1 and suppression of FPN expression. Iron influx and efflux assays in vitro confirmed that iron homeostasis in astrocytes and microglia is differentially regulated by these cytokines. In particular, TNF-α caused an increase in iron uptake and retention by both astrocytes and microglia, while TGF-β1 promoted iron efflux from astrocytes but caused iron retention in microglia. These data suggest that these two cytokines, which are expressed in CNS inflammation in injury and disease, can have profound and divergent effects on iron homeostasis in astrocytes and microglia. 相似文献
5.
Santos MM Miranda CJ Levy JE Montross LK Cossée M Sequeiros J Andrews N Koenig M Pandolfo M 《Cerebellum (London, England)》2003,2(2):146-153
Friedreich ataxia (FRDA), the most common autosomal recessive inherited ataxic disorder, is the consequence of deficiency of the mitochondrial protein frataxin, typically caused by homozygous intronic GAA expansions in the corresponding gene. The yeast frataxin homologue (yfh1p) is required for cellular respiration. Yfh1p appears to regulate mitochondrial iron homeostasis and protect from free radical toxicity. Complete loss of frataxin in knockout mice leads to early embryonic lethality, indicating an important role for frataxin during development. Heterozygous littermates with partial frataxin deficiency are apparently healthy and have no obvious phenotype. Here we evaluate iron metabolism and sensitivity to dietary and parenteral iron loading in heterozygote frataxin knockout mice (Fx(+/-)). Iron concentrations in the liver, heart, pancreas and spleen, and cellular iron distribution patterns were compared between wild type and Fx(+/-) mice. Response to parenteral iron challenge was not different between Fx(+/-) mice and wild type littermates, while sporadic iron deposits were observed in the hearts of dietary iron-loaded Fx(+/-) mice. Finally, we evaluated the effect of partial frataxin deficiency on susceptibility to cardiac damage in the mouse model of hereditary hemochromatosis (HH), the Hfe knockout mice. HH, an iron overload disease, is one of the most frequent genetic diseases in populations of European origin. By breeding Hfe(-/-) with Fx(+/-) mice, we obtained compound mutant mice lacking both Hfe and one frataxin allele. Sparse iron deposits in areas of mild to moderate cardiac fibrosis were found in the majority of these mice. However, they did not develop any neurological symptoms. Our studies indicate an association between frataxin deficiency, iron deposits and cardiac fibrosis, but no obvious association between iron accumulation and neurodegeneration similar to FRDA could be detected in our model. In addition, these results suggest that frataxin mutations may have a modifier role in HH, that predisposes to cardiomyopathy. 相似文献
6.
M B Delatycki J Camakaris H Brooks T Evans-Whipp D R Thorburn R Williamson S M Forrest 《Annals of neurology》1999,45(5):673-675
Friedreich ataxia (FRDA) is due to mutations in the FRDA gene (FRDA). When the gene homologous to FRDA is knocked out in yeast, there is accumulation of iron in mitochondria and reduced respiratory function. So far, there is only indirect evidence to support the hypothesis that FRDA is due to accumulation of mitochondrial iron leading to increased production of free radicals. We show here that mitochondrial iron is significantly higher in fibroblasts from patients with FRDA than in control fibroblasts. This is the first direct evidence that the findings in yeast are reproducible in cells from patients with FRDA. 相似文献
7.
Nachbauer W Hering S Seifert M Steinkellner H Sturm B Scheiber-Mojdehkar B Reindl M Strasak A Poewe W Weiss G Boesch S 《Cerebellum (London, England)》2011,10(4):763-769
Friedreich ataxia (FRDA) is an autosomal recessive inherited neurodegenerative disorder leading to reduced expression of the mitochondrial protein frataxin. Previous studies showed frataxin upregulation in FRDA following treatment with recombinant human erythropoietin (rhuEPO). Dose-response interactions between frataxin and rhuEPO have not been studied until to date. We administered escalating rhuEPO single doses (5,000, 10,000 and 30,000?IU) in monthly intervals to five adult FRDA patients. Measurements of frataxin, serum erythropoietin levels, iron metabolism and mitochondrial function were carried out. Clinical outcome was assessed using the "Scale for the assessment and rating of ataxia". We found maximal erythropoietin serum concentrations 24?h after rhuEPO application which is comparable to healthy subjects. Frataxin levels increased significantly over 3?months, while ataxia rating did not reveal clinical improvement. All FRDA patients had considerable ferritin decrease. NADH/NAD ratio, an indicator of mitochondrial function, increased following rhuEPO treatment. In addition to frataxin upregulation in response to continuous low-dose rhuEPO application shown in previous studies, our results indicate for a long-lasting frataxin increase after single high-dose rhuEPO administration. To detect frataxin-derived neuroprotective effects resulting in clinically relevant improvement, well-designed studies with extended time frame are required. 相似文献
8.
Friedreich's ataxia (FRDA), an autosomal recessive disorder, is characterized by spinocerebellar degeneration and cardiomyopathy. Here we explore some of the putative mechanisms underlying the cardiomyopathy in FRDA that have been elucidated using different experimental models. FRDA is characterized by a deficiency in frataxin, a protein vital in iron handling. Iron accumulation, lack of functional iron-sulphur clusters, and oxidative stress seem to be among the most important consequences of frataxin deficiency explaining the cardiac abnormalities in FRDA. 相似文献
9.
Natalie Serkova Paul Donohoe Sven Gottschalk Carsten Hainz Claus U Niemann Philip E Bickler Lawrence Litt Leslie Z Benet Dieter Leibfritz Uwe Christians 《Journal of cerebral blood flow and metabolism》2002,22(3):342-352
The authors evaluated and compared the metabolic effects of cyclosporin A in the rat brain during normoxia and hypoxia/reperfusion. Ex vivo 31P magnetic resonance spectroscopy experiments based on perfused rat brain slices showed that under normoxic conditions, 500 microg/L cyclosporin A significantly reduced mitochondrial energy metabolism (nucleotide triphosphate, 83 +/- 9% of controls; phosphocreatine, 69 +/- 9%) by inhibition of the Krebs cycle (glutamate, 77 +/- 5%) and oxidative phosphorylation (NAD+, 65 +/- 14%) associated with an increased generation of reactive oxygen species (285 +/- 78% of control). However, the same cyclosporin A concentration (500 microg/L) was found to be the most efficient concentration to inhibit the hypoxia-induced mitochondrial release of Ca2+ in primary rat hippocampal cells with cytosolic Ca2+ concentrations not significantly different from normoxic controls. Addition of 500 microg/L cyclosporin A to the perfusion medium protected high-energy phosphate metabolism (nucleotide triphosphate, 11 +/- 15% of control vs. 35 +/- 9% with 500 microg/L cyclosporin A) and the intracellular pH (6.2 +/- 0.1 control vs. 6.6 +/- 0.1 with cyclosporin A) in rat brain slices during 30 minutes of hypoxia. Results indicate that cyclosporin A simultaneously decreases and protects cell glucose and energy metabolism. Whether the overall effect was a reduction or protection of cell energy metabolism depended on the concentrations of both oxygen and cyclosporin A in the buffer solution. 相似文献
10.
Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier 总被引:10,自引:0,他引:10
Wu LJ Leenders AG Cooperman S Meyron-Holtz E Smith S Land W Tsai RY Berger UV Sheng ZH Rouault TA 《Brain research》2004,1001(1-2):108-117
Iron homeostasis in the mammalian brain is an important and poorly understood subject. Transferrin-bound iron enters the endothelial cells of the blood-brain barrier from the systemic circulation, and iron subsequently dissociates from transferrin to enter brain parenchyma by an unknown mechanism. In recent years, several iron transporters, including the iron importer DMT1 (Ireg1, MTP, DCT1) and the iron exporter ferroportin (SLC11A3, Ireg, MTP1) have been cloned and characterized. To better understand brain iron homeostasis, we have characterized the distribution of ferroportin, the presumed intestinal iron exporter, and have evaluated its potential role in regulation of iron homeostasis in the central nervous system. We discovered using in situ hybridization and immunohistochemistry that ferroportin is expressed in the endothelial cells of the blood-brain barrier, in neurons, oligodendrocytes, astrocytes, and the choroid plexus and ependymal cells. In addition, we discovered using techniques of immunoelectron microscopy and biochemical purification of synaptic vesicles that ferroportin is associated with synaptic vesicles. In the blood-brain barrier, it is likely that ferroportin serves as a molecular transporter of iron on the abluminal membrane of polarized endothelial cells. The role of ferroportin in synaptic vesicles is unknown, but its presence at that site may prove to be of great importance in neuronal iron toxicity. The widespread representation of ferroportin at sites such as the blood-brain barrier and synaptic vesicles raises the possibility that trafficking of elemental iron may be instrumental in the distribution of iron in the central nervous system. 相似文献