共查询到17条相似文献,搜索用时 46 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.
Jennifer A. Morral Ashley N. Davis Jiang Qian Benjamin B. Gelman Arnulf H. Koeppen 《Acta neuropathologica》2010,120(1):97-108
Friedreich’s ataxia (FRDA) causes a complex neuropathological phenotype with characteristic lesions of dorsal root ganglia
(DRG); dorsal spinal roots; dorsal nuclei of Clarke; spinocerebellar and corticospinal tracts; dentate nuclei; and sensory
nerves. This report presents a systematic morphological analysis of sural nerves obtained by autopsy of six patients with
genetically confirmed FRDA. The outstanding lesion consisted of lack of myelinated fibers whereas axons were present in normal
numbers. On cross-sections, only 11% of all class III-β-tubulin-positive axons were myelinated in FRDA, contrasting with 36%
in normal control nerves. Despite their paucity, thin myelinated fibers assembled compact sheaths containing the peripheral
myelin proteins PMP-22, P0, and myelin basic protein. The nerves displayed major modifications in Schwann cells that were apparent by laminin 2 and
S100α immunocytochemistry. Few S100α-immunoreactive cells remained detectable whereas laminin 2 reaction product was abundant.
The normal honeycomb-like distribution of laminin 2 around myelinated fibers was replaced by confluent regions of reaction
product that enveloped clusters of closely apposed thin axons. Electron microscopy not only confirmed the lack of myelin but
also showed abnormal Schwann cells and axons. Ferritin localized to normal Schwann cell cytoplasm. In the sensory nerves of
patients with FRDA, the distribution of this protein strongly resembled laminin 2, but there was no net increase of the total
ferritin-reactive area. Ferroportin reaction product occurred in all axons of sural nerves in FRDA, which was at variance
with dorsal spinal roots. In the pathogenesis of sensory neuropathy in FRDA, two mechanisms are likely: hypomyelination due
to faulty interaction between axons and Schwann cells; and slow axonal degeneration. Neurons of DRG, satellite cells, Schwann
cells, and axons of sensory nerves and dorsal spinal roots derive from the neural crest, and hypomyelination in FRDA may be
attributed to defects of regulation or migration of shared precursor cells. Sural nerves in FRDA showed no convincing change
in ferritin and ferroportin, militating against local iron dysmetabolism. The result stands out in contrast to the previously
reported changes in dorsal spinal roots of patients with FRDA. 相似文献
3.
Hayer Stefanie Nicole Liepelt Inga Barro Christian Wilke Carlo Kuhle Jens Martus Peter Schöls Ludger 《Journal of neurology》2020,267(5):1420-1430
Journal of Neurology - To assess neurofilaments as neurodegenerative biomarkers in serum of patients with Friedreich’s ataxia. Single molecule array measurements of neurofilament light (NfL)... 相似文献
4.
Lack of frataxin in Friedreich’s ataxia (FRDA) causes a complex neurological and pathological phenotype. Progressive atrophy
of the dentate nucleus (DN) is a major intrinsic central nervous system lesion. Antibodies to neuron-specific enolase (NSE),
calbindin, glutamic acid decarboxylase (GAD), and vesicular glutamate transporters 1 and 2 (VGluT1, VGluT2) allowed insight
into the disturbed synaptic circuitry of the DN. The available case material included autopsy specimens of 24 patients with
genetically defined FRDA and 14 normal controls. In FRDA, the cerebellar cortex revealed intact Purkinje cell somata and dendrites
as assessed by calbindin immunoreactivity. The DN, however, displayed severe loss of large NSE-reactive neurons. Small neurons
remained intact. Labeling of Purkinje cells, basket fibers, Golgi neurons, and Golgi axonal plexuses with antibodies to GAD
indicated normal intrinsic circuitry of the cerebellar cortex involving γ-aminobutyric acid (GABA). In contrast, the DN displayed
severe loss of GABA-ergic terminals and formation of GAD- and calbindin-reactive grumose degeneration. The surviving small
GAD-positive DN neurons provided normal GABA-ergic terminals to intact inferior olivary nuclei. The olives also received normal
glutamatergic terminals as shown by VGluT2-reactivity. VGluT1-immunocytochemistry of the cerebellar cortex confirmed normal
glutamatergic input to the molecular layer by parallel fibers and the granular layer by mossy fibers. VGluT2-immunoreactivity
visualized normal climbing fibers and mossy fiber terminals. The DN, however, showed depletion of VGluT1- and VGluT2-reactive
terminals arising from climbing and mossy fiber collaterals. The main functional deficit underlying cerebellar ataxia in FRDA
is defective processing of inhibitory and excitatory impulses that converge on the large neurons of the DN. The reason for
the selective vulnerability of these nerve cells remains elusive. 相似文献
5.
Lower limb spasticity compromises the independence of people with Friedreich’s ataxia (FRDA). This study sought to examine lower limb spasticity in FRDA in order to offer new insight as to the best approach and timing of spasticity management. Gastrocnemius and soleus spasticity and muscle length were measured by the Modified Tardieu Scale (MTS) in 31 participants with typical and late-onset FRDA. Relationships between the MTS and the Friedreich Ataxia Rating Scale (FARS), Functional Independence Measure (FIM), and disease duration were analysed. Differences between ambulant (n = 18) and non-ambulant (n = 13) participants were also examined. All participants had spasticity in at least one muscle, and 38.9% of ambulant and 69.2% of non-ambulant participants had contracture in one or both of their gastrocnemius muscles. Significant negative correlations were found between both gastrocnemius and soleus angle of catch and the FARS score. The FIM score also demonstrated significant correlations with gastrocnemius muscle length and angle of catch. Gastrocnemius and soleus spasticity and contracture is apparent in people with FRDA. Spasticity is evident early in the disease and in ambulant participants. Management of spasticity and reduced muscle length should be considered in people with FRDA at disease onset to optimise function. 相似文献
6.
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
7.
Marcondes C. França Jr Anelyssa D’Abreu Clarissa L. Yasuda Luciana Cardoso Bonadia Marilza Santos da Silva Anamarli Nucci Iscia Lopes-Cendes Fernando Cendes 《Journal of neurology》2009,256(7):1114-1120
Friedreich’s ataxia (FA) is the most frequent autosomal recessive ataxia and essentially considered a disease of the dorsal
root ganglia and spinal cord. It is caused by homozygous GAA expansions in the Frataxin gene in most cases. Although only a few studies have addressed cerebral involvement in FA, cognitive symptoms have lately
been emphasized. To evaluate brain damage in vivo, we employed whole-brain VBM and analysis of pre-defined regions of interest
(ROIs) over the cerebellum to compare 24 patients with 24 age-and-sex-matched normal controls. 1H-MRS of deep cerebral white matter (WM) was subsequently performed. Mean age of patients was 28 years (range 14–45), mean
duration of disease was 14 years (range 5–28) and 11 were men. Mean length of shorter (GAA1) and longer (GAA2) alleles were
735 and 863, respectively. VBM analysis identified WM atrophy in the posterior cyngulate gyrus, paracentral lobule and middle
frontal gyrus. ROIs over the infero-medial cerebellar hemispheres and dorsal brainstem presented gray matter atrophy, which
correlated with duration of disease (r = −0.4). NAA/Cr ratios were smaller among patients (P = 0.006), but not Cho/Cr (P = 0.08). Our results provide evidence of axonal damage in the cerebellum, brainstem and subcortical WM in FA. This suggests
that neuronal dysfunction is more widespread than previously thought in FA. 相似文献
8.
Friedreich ataxia (FRDA) is an autosomal recessive, multi-systemic degenerative disease that results from reduced synthesis of the mitochondrial protein frataxin. Frataxin has been intensely studied since its deficiency was linked to FRDA in 1996. The defining properties of frataxin – (i) the ability to bind iron, (ii) the ability to interact with, and donate iron to, other iron-binding proteins, and (iii) the ability to oligomerize, store iron and control iron redox chemistry – have been extensively characterized with different frataxin orthologs and their interacting protein partners. This very large body of biochemical and structural data [reviewed in (Bencze et al., 2006)] supports equally extensive biological evidence that frataxin is critical for mitochondrial iron metabolism and overall cellular iron homeostasis and antioxidant protection [reviewed in (Wilson, 2006)]. However, the precise biological role of frataxin remains a matter of debate. Here, we review seminal and recent data that strongly link frataxin to the synthesis of iron–sulfur cluster cofactors (ISC), as well as controversial data that nevertheless link frataxin to additional iron-related processes. Finally, we discuss how defects in ISC synthesis could be a major (although likely not unique) contributor to the pathophysiology of FRDA via (i) loss of ISC-dependent enzymes, (ii) mitochondrial and cellular iron dysregulation, and (iii) enhanced iron-mediated oxidative stress. This article is part of a Special Issue entitled ‘Mitochondrial function and dysfunction in neurodegeneration’. 相似文献
9.
Schöls L Zange J Abele M Schillings M Skipka G Kuntz-Hehner S van Beekvelt MC Colier WN Müller K Klockgether T Przuntek H Vorgerd M 《Journal of neural transmission (Vienna, Austria : 1996)》2005,112(6):789-796
Summary. Impaired oxidative phosphorylation is a crucial factor in the pathogenesis of Friedreichs ataxia (FA). L-carnitine and creatine are natural compounds that can enhance cellular energy transduction. We performed a placebo-controlled triple-phase crossover trial of L-carnitine (3g/d) and creatine (6.75g/d) in 16 patients with genetically confirmed FA. Primary outcome measures were mitochondrial ATP production measured as phosphocreatine recovery by 31Phosphorus magnetic resonance spectroscopy, neurological deficits assessed by the international co-operative ataxia rating scale and cardiac hypertrophy in echocardiography. After 4 months on L-carnitine phosphocreatine recovery was improved compared to baseline (p<0.03, t-test) but comparison to placebo and creatine effects did not reach significance (p=0.06, F-test). Ataxia rating scale and echocardiographic parameters remained unchanged. Creatine had no effect in FA patients. L-carnitine is a promising substance for the treatment of FA patients, and larger trials are warranted.Both authors contributed equally to this work 相似文献
10.
T. Klopstock S. Chahrokh-Zadeh E. Holinski-Feder A. Meindl T. Gasser D. Pongratz W. Müller-Felber 《Acta neuropathologica》1999,97(2):139-142
Friedreich’s ataxia (FA) is most frequently caused by intronic trinucleotide repeat expansions in the frataxin gene on chromosome
9. The broad clinical spectrum includes late-onset FA (LOFA) and FA with retained reflexes (FARR). The size of the GAA expansions
accounts for most, but not all, of the clinical variability. We report the unusual occurrence of LOFA and FARR in two siblings
of patients with classical early-onset FA in two families. In spite of the markedly different course of the disease, the respective
siblings harboured GAA repeat expansions of similar size in leucocytes. Since haplotype-related variability is not likely
among siblings, we suppose that this intrafamilial phenotype variability is due to somatic mosaicism, with the more severely
affected siblings harbouring the larger expansions in spinal cord and other affected tissues. In view of these results, genetic
counseling and predictions on the course of FA are particularly difficult, even if an expansion mutation is found.
Received: 5 May 1998 / Revised, accepted: 15 July 1998 相似文献
11.
M. Armani M. Zortea E. Pastorello S. Lombardi S. Tonello L. Zuliani M. T. Rigoni C. P. Trevisan 《Neurological sciences》2006,27(2):140-142
Abstract Diagnostic evaluation of two sisters affected by ataxia, with similar age of onset, revealed a characteristic trinucleotide
expansion in the Friedreich’s ataxia (FRDA) locus and two different phenotypic presentations. At onset the elder sister had
retained deep tendon reflexes (FARR), while the younger sister presented classic FRDA. The GAA expansion in the patients’
alleles proved to be similar in both siblings, ruling out that age at onset and clinical heterogeneity could be due to different
FRDA mutations. On the whole, clinical and genetic data on these patients confirmed that FARR is a variant phenotype of FRDA. 相似文献
12.
Acquaviva F Castaldo I Filla A Giacchetti M Marmolino D Monticelli A Pinelli M Saccà F Cocozza S 《Cerebellum (London, England)》2008,7(3):360-365
Friedreich’s ataxia is an autosomal recessive neurodegenerative disease that is due to the loss of function of the frataxin
protein. The molecular basis of this disease is still a matter of debate and treatments have so far focused on managing symptoms.
Drugs that can increase the amount of frataxin protein offer a possible therapy for the disease. One such drug is recombinant
human erythropoietin (rhu-EPO). Here, we report the effects of rhu-EPO on frataxin mRNA and protein in primary fibroblast
cell cultures derived from Friedreich’s ataxia patients. We observed a slight but significant increase in the amount of frataxin
protein. Interestingly, we did not observe any increase in the messenger RNA expression at any of the times and doses tested,
suggesting that the regulatory effects of rhu-EPO on the frataxin protein was at the post-translational level. These findings
could help the evaluation of the treatment with erythropoietin as a potential therapeutic agent for Friedreich’s ataxia. 相似文献
13.
A. Larnaout S. Belal M. Zouari M. Fki C. Ben Hamida H. H. Goebel M. Ben Hamida F. Hentati 《Acta neuropathologica》1997,93(6):633-637
The neuropathological findings in a Tunisian patient with Friedreich’s ataxia with vitamin E deficiency are reported. The
main histological changes are: (1) spinal sensory system demyelination with neuronal atrophy, axonal spheroids and corpora
amylacea; (2) neuronal lipofuscin accumulation in the third cortical layer of the cerebral cortex, thalamus, lateral geniculate
body, twelfth and ambiguus nuclei, spinal horns and posterior root ganglia. Ultrastructurally, the lipopigments were of uniform
granularity without lipid droplets.
Received: 20 May 1996 / Revised, accepted: 6 October 1996 相似文献
14.
15.
Giuseppe De Michele Alessandro Filla Chiara Criscuolo Valentina Scarano Francesca Cavalcanti Luigi Pianese Antonella Monticelli Sergio Cocozza 《Journal of neurology》1998,245(3):166-168
We studied the factors that might influence onset age in Friedreich’s ataxia in 41 cases (20 male, 21 female) homozygous
for GAA expansion on the first intron of X25 gene. Patients came from 18 multiplex families (13 couples, 5 triplets). Mean age (SD) was 18.1 (8.9) years and did not
differ by gender. Onset age and the sizes of the smaller (GAA1) and the larger (GAA2) allele in each pair showed high intrafamily
correlation. We found an inverse correlation between age at onset and GAA1 size, but not between age at onset and GAA2 size.
Stepwise multiple regression of onset age on GAA1 size, sibling onset age, and GAA2 size showed that GAA1 accounts for 73%
of onset age variance, and sibling onset age for an additional 13%. The study demonstrates that, in addition to GAA expansion
size, other environmental or genetic familial factors influence disease expression.
Received: 30 June 1997 Received in revised form: 20 November 1997 Accepted: 8 December 1997 相似文献
16.
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
17.
Siddappa AJ Rao RB Wobken JD Leibold EA Connor JR Georgieff MK 《Journal of neuroscience research》2002,68(6):761-775
The perinatal brain requires a tightly regulated iron transport system. Iron regulatory proteins (IRPs) 1 and 2 are cytosolic proteins that regulate the stability of mRNA for the two major cellular iron transporters, transferrin receptor (TfR) and divalent metal transporter-1 (DMT-1). We studied the localization of IRPs, their change in expression during perinatal development, and their relationship to TfR and DMT-1 in rat brain between postnatal days (PND) 5 and 15. Twelve-micron frozen coronal sections of fixed brain tissue were obtained from iron-sufficient Sprague-Dawley rat pups on PND 5, 10, and 15, and were visualized at 20 to 1,000x light microscopy for diaminobenzidine activity after incubation with specific primary IRP-1, IRP-2, DMT-1, and TfR antibodies and a universal biotinylated secondary and tertiary antibody system. IRP and transport protein expression increased in parallel over time. IRP1, IRP2, and DMT-1 were partially expressed in the choroid plexus epithelial cells at PND 5 and 10, and fully expressed at PND 15. The cerebral blood vessels and ependymal cells strongly expressed IRP1, IRP2, and DMT-1 as early as PND 5. Substantive TfR staining was not seen in the choroid plexus or ependyma until PND 15. Glial and neuronal expression of IRP1, IRP2, DMT-1, and TfR in cortex, hippocampal subareas and striatum increased over time, but showed variability in cell number and intensity of expression based on brain region, cell type, and age. These developmental changes in IRP and transporter expression suggest potentially different time periods of brain structure vulnerability to iron deficiency or iron overload. 相似文献