Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The distribution of two calcium-binding proteins, calbindin D28k (CaBP) and parvalbumin (PV), was investigated by immunohistochemistry in the brains of three individuals dying of nonneurologic illness and three patients with spinocerebellar ataxia-1 (SCA-1). SCA-1 has recently been proven to be due to an unstable CAG repeat mutation on chromosome 6. In the cerebellum of control individuals the Purkinje cells showed strong immunoreactivity to CaBP. Other cells were CaBP-negative. Parvalbumin was highly localized to Purkinje, basket, stellate, and Golgi cells. All surviving Purkinje cells in SCA-1 were strongly immunoreactive to CaBP. The number of PV-immunoreactive Purkinje cells was markedly reduced in SCA-1. In addition, there was a significant decrease in the intensity of PV immunostaining within the individual Purkinje cells compared with controls. However, in the hippocampus, temporal cortex, and lateral geniculate scattered PV-positive neurons were seen in SCA-1 patients, similar to those in controls. The present results suggest that the decreased PV-immunoreactivity in the surviving Purkinje cells in SCA-1 may reflect biochemical alterations preceding Purkinje cell degeneration.
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PMID:Decreased parvalbumin immunoreactivity in surviving Purkinje cells of patients with spinocerebellar ataxia-1. 871 87

The role of neurotrophin-3 (NT3) during sensory neuron development was investigated in transgenic mice overexpressing NT3 under the control of the promoter and enhancer regions of the nestin gene, an intermediate filament gene widely expressed in the developing nervous system. Most of these mice died during the first postnatal day, and all showed severe limb ataxia suggestive of limb proprioceptive dysfunction. Tracing and histological analyses revealed a complete loss of spindles in limb muscles, absence of peripheral and central Ia projections, and lack of cells immunoreactive to parvalbumin in the dorsal root ganglion (DRG). Despite these deficits, there was no neuronal loss in the DRG of these mice. At birth, transgenic DRG showed increased neuron numbers, and displayed a normal proportion of neurons expressing substance P, calcitonin gene-related peptide and the NT3 receptor trkC. Transgenic dorsal roots exhibited an increased number of axons at birth, indicating that all sensory neurons in transgenic mice projected to the dorsal spinal cord. Despite the absence of central Ia afferents reaching motorneurons, several sensory fibers were seen projecting towards ectopic high levels of NT3 in the midline of transgenic spinal cords. These findings suggest novel roles for NT3 in differentiation of proprioceptive neurons, target invasion and formation of Ia projections which are independent from its effects on neuronal survival.
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PMID:Limb proprioceptive deficits without neuronal loss in transgenic mice overexpressing neurotrophin-3 in the developing nervous system. 921 2

Earlier we have shown alterations in immunoreactivity (IR) to the calcium-binding proteins parvalbumin (PV) and calbindin D-28k (CaB) in surviving Purkinje cells of patients with spinocerebellar ataxia-1 (SCA-1). In the present study we determined PV and CaB expression (by immunohistochemical and immunoblot analyses) in Purkinje cells of transgenic mice (TM) expressing the human SCA-1 gene with an expanded (line B05) and normal (line A02) CAG tract, as well as in age-matched nontransgenic mice (nTM). Heterozygotes in the B05 line develop progressive ataxia beginning around 12 weeks of age. A02 animals are phenotypically indistinguishable from wild-type (nontransgenic) animals. In the cerebella of 8-, 9-, and 12-week-old TM-B05 there was a progressive decrease in PV IR in Purkinje cells compared with nTM and TM-A02. Parvalbumin immunostaining in interneurons was well preserved in all groups. A progressive decrease was also observed in CaB IR in Purkinje cells of 8-, 9-, and 12-week-old TM-B05. Cerebellar Purkinje cells of 6-week-old TM-B05, which exhibit no ataxia and even lack demonstrable Purkinje cell loss, also revealed reduction in PV IR. This change was matched by a significant decrease in the amount of cerebellar PV in 6-week-old TM-B05 as determined by Western blot analysis. Calbindin D-28K immunohistochemistry did not detect any marked changes in CaB IR within Purkinje cells at 4 weeks. However, at 6 weeks immunostaining and immunoblot analysis revealed a significant decrease in CaB in TM-B05 compared with controls. These data suggest that decreased levels of calcium-binding proteins in Purkinje cells in SCA-1 transgenic mice may cause alteration in Ca2+ homeostasis.
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PMID:Reduced immunoreactivity to calcium-binding proteins in Purkinje cells precedes onset of ataxia in spinocerebellar ataxia-1 transgenic mice. 944 66

Spinocerebellar ataxia-1 (SCA-1), like other polyglutamine diseases, is associated with aggregation of mutant protein ataxin-1 in the nuclei of susceptible neurons. The role of ataxin-1 aggregates in the pathogenesis of susceptible neurons, especially cerebellar Purkinje cells, is unknown. The present study was initiated to determine the temporal relationship between ataxin-1 aggregation and the sequence of specific biochemical changes in Purkinje cells in SCA-1 transgenic mice (TM). Earlier, we demonstrated that SCA-1 TM with no Purkinje cell loss and no alterations in home cage behavior show decreased expression of calcium-binding proteins calbindin-D28k (CaB) and parvalbumin (PV) in Purkinje cells. To determine if increased expression of mutant ataxin-1 in TM is also associated with earlier biochemical changes in Purkinje cells, both heterozygous and homozygous (B05 line of SCA-1) TM were used. The age of onset of ataxia in SCA-1 TM was at 12 weeks in heterozygotes and 6 weeks in homozygotes. In 6 week old heterozygous TM, Western blot analysis of growth associated protein 43 (GAP-43) and synaptophysin revealed no significant alterations as compared with the age-matched nontransgenic mice (nTM), whereas CaB was significantly reduced. beta-III-Tubulin was used as a specific Purkinje cell marker protein, immunohistochemical localization showed strong beta-III-tubulin immunoreactivity (IR) in Purkinje cells in 6 week old heterozygous TM, whereas CaB and PV IR were markedly reduced in the same neurons (double immunofluorescence staining). Most Purkinje cells from heterozygous (12 weeks old) and homozygous (6 weeks old) TM contained ataxin-1 nuclear inclusions (NIs). Cells with and without visible NIs revealed reduced PV and CaB IR; however, the changes were overtly more severe in cells with visible NIs. In contrast, the same cells were strongly immunoreactive to beta-III-tubulin. CaB, which is also present in the nucleus, colocalized with ataxin-1 and ubiquitin positive NIs. Further, RT-PCR analysis of CaB mRNA in the cerebellum in 6 week old heterozygous TM demonstrated a significant decrease in mRNA in comparison with the aged-matched nTM. These data suggest that there are selective alterations in the expression of CaB and PV in Purkinje cells which possibly occur earlier than ataxin-1 aggregation. Further, we speculate that ataxin-1 aggregates may not be toxic in general; however, they may deplete specific proteins essential for Purkinje cell viability in SCA-1 TM.
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PMID:Relationship between ataxin-1 nuclear inclusions and Purkinje cell specific proteins in SCA-1 transgenic mice. 1072 95

Spinocerebellar ataxia type 6 (SCA6) was recently identified as a form of autosomal dominant spinocerebellar ataxia associated with a small CAG repeat expansion of the gene encoding an alpha 1 A-voltage-dependent calcium channel gene subunit on chromosome 19p13. In this study 50-microm-thick sections of cerebellar tissue from one patient with SCA6 were subjected to free-floating immunohistochemical staining with calbindin-D and parvalbumin antibodies. Severe loss of Purkinje cells was found, particularly in the vermis, and various morphological changes in Purkinje cells and their dendritic arborizations were demonstrated. Many of the remaining Purkinje cells were found to have heterotopic, irregularly shaped nuclei, an unclear cytoplasmic membrane outline, and somatic sprouts. Increased numbers of spine-like protrusions from swelling dendritic arborizations were found in the molecular layer. The axonal arrangement was disordered, and many torpedos were found in the granular layer and white matters. These morphological changes are completely different from those observed in paraneoplastic cerebellar degeneration (PCD) and multiple system atrophy (MSA) and are considered to be related to the genetic abnormality that causes abnormal development of Purkinje cells.
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PMID:Morphological Purkinje cell changes in spinocerebellar ataxia type 6. 1098 94

The pogo mouse is a novel neurological mutant, which was discovered, in an inbred strain (KJR/MsKist) derived from a Korean wild mouse. The pathological manifestations include difficulty in maintaining normal posture, failures of interlimb coordination and the inability to walk straight. The ataxia is first apparent from about 2 weeks of age and progresses throughout life. The mutation is inherited as an autosomal recessive trait. In this report, we describe abnormalities in the pogo/pogo cerebellum. Nissl staining shows that the pogo/pogo cerebellum is normal in size and lobulation. Similarly, immunocytochemical staining for a granule cell marker, 10B5, shows no differences in the thickness of the granular layer between pogo/pogo homozygote and pogo/+ heterozygote littermate controls. By using anti-parvalbumin immunocytochemistry, the cells of molecular layer of the pogo/pogo cerebellum also appeared similar in distribution as compared to normal wild type mouse. In anti-neurofilament immunocytochemistry, the basket cells axons of the pogo/pogo cerebellum appeared normal. Purkinje cell abnormalities were identified by using anti-calbindin D immunocytochemistry. In 120-day-old pogo/pogo mutant mice there was a loss of Purkinje cells throughout the cerebellar vermis. Furthermore, the somata and dendrites were extensively vacuolated in the pogo/pogo Purkinje cells and the primary dendrites were frequently swollen. Focal axonal swellings were commonly observed in the Purkinje cell axons of pogo/pogo mutant mice as they traversed the granular layer. These data suggest that the progressive ataxia seen in pogo mice may be due to a failure of normal Purkinje cell activity.
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PMID:Abnormalities in cerebellar Purkinje cells in the novel ataxic mutant mouse, pogo. 1115 61

Spinocerebellar ataxia type 2 is caused by a polyglutamine stretch in the protein ataxin-2 that is due to an expansion of a CAG repeat in the spinocerebellar ataxia-2 gene. The function of wild-type ataxin-2 has not been clarified. A widespread distribution of this protein throughout the brain has been reported. We examined the expression of ataxin-2 in cortical cerebellar cells of the adult rat. We performed a single label immunohistochemical study of ataxin-2 and a single label immunofluorescence study of ataxin-2 and zebrin on adjacent sections, to compare the distribution of the observed parasagittal band pattern. We also performed a double label immunofluorescence study of ataxin-2 and one of each parvalbumin, calbindin, and calretinin. Single label studies revealed that between 50% and 70% of the Purkinje cells express ataxin-2. The abundance of ataxin-2 was different between hemisphere and vermis, with a clear prevalence for the former. Furthermore, the distribution of ataxin-2-positive Purkinje cells showed a peculiar alternating parasagittal band pattern. Among the other cortical cerebellar cells only basket and granule cells showed ataxin-2 staining. Our dual label studies showed that about 50% of calbindin and more than 70% of parvalbumin-immunoreactive Purkinje cells were also labeled for ataxin-2. The uneven distribution of ataxin-2 expression in the Purkinje cell layer does not support the hypothesized link between ataxin-2 content and cell vulnerability. The differences in ataxin-2 expression among the cell types of cerebellar cortex, on the other hand, suggest a possible correlation between ataxin-2 content and cell function.
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PMID:Localization of ataxin-2 within the cerebellar cortex of the rat. 1171 70

The RUNX transcription factors are important regulators of linage-specific gene expression in major developmental pathways. Recently, we demonstrated that Runx3 is highly expressed in developing cranial and dorsal root ganglia (DRGs). Here we report that within the DRGs, Runx3 is specifically expressed in a subset of neurons, the tyrosine kinase receptor C (TrkC) proprioceptive neurons. We show that Runx3-deficient mice develop severe limb ataxia due to disruption of monosynaptic connectivity between intra spinal afferents and motoneurons. We demonstrate that the underlying cause of the defect is a loss of DRG proprioceptive neurons, reflected by a decreased number of TrkC-, parvalbumin- and beta-galactosidase-positive cells. Thus, Runx3 is a neurogenic TrkC neuron-specific transcription factor. In its absence, TrkC neurons in the DRG do not survive long enough to extend their axons toward target cells, resulting in lack of connectivity and ataxia. The data provide new genetic insights into the neurogenesis of DRGs and may help elucidate the molecular mechanisms underlying somatosensory-related ataxia in humans.
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PMID:The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons. 1209 46

Scrapie is a prion disease in small ruminants that manifests itself with neurological clinical signs amongst which are ataxia and tremors. These signs can be explained partially by an imbalance in central inhibitory innervation. The study of the brain's inhibitory neuronal GABAergic populations and of their extracellular matrix has been used to define, in part, the pathogenesis of human prion diseases and scrapie models in rodents. The brain's distribution of neuronal GABAergic subpopulations has been monitored carefully using, as markers, antibodies against the calcium binding proteins parvalbumin and calbindin D-28K. The distribution of this perineuronal net marker was evaluated by means of affinity histochemistry with W. floribunda agglutinin. These techniques were performed on the brains of nine scrapie-positive sheep and on four infection-free sheep. These animals had undergone previously a clinical follow-up as well as a lesion profile and an immunohistochemical profile of the scrapie-associated prion protein deposition in the brain. The study of calcium-binding proteins revealed an alteration of the parvalbumin positive GABAergic neuronal subpopulation. In scrapie-positive cases, a reduction in stained neuronal perykaria was observed, along with a marked reduction of neurite labelling. This finding was noticeable in regions such as the neocortex, particularly the motor frontal cortex, and was concomitant with a moderate PrPsc deposition and a mild degree of lesion. No changes were observed in the extracellular matrix study. The results of the present study provide a partial explanation for the mechanisms of scrapie clinical signs due to a disturbance of the parvalbumin-positive inhibitory neuronal population.
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PMID:Assessment of calcium-binding proteins (Parvalbumin and Calbindin D-28K) and perineuronal nets in normal and scrapie-affected adult sheep brains. 1682 73

The role of the cerebellum has been increasingly recognized not only in motor control but in sensory, cognitive and emotional learning and regulation. Purkinje cells, being the sole output from the cerebellar cortex, occupy an integrative position in this network. Plasticity at this level is known to critically involve calcium signaling. In the last few years, electrophysiological study of genetically engineered mice has demonstrated the topical role of several genes encoding calcium-binding proteins (calretinin, calbindin, parvalbumin). Specific inactivation of these genes results in the emergence of a fast network oscillation (ca. 160 Hz) throughout the cerebellar cortex in alert animals, associated with ataxia. This oscillation is produced by synchronization of Purkinje cells along the parallel fiber beam. It behaves as an electrophysiological arrest rhythm, being blocked by sensorimotor stimulation. Pharmacological manipulations showed that the oscillation is blocked by GABA(A) and NMDA antagonists as well as gap junction blockers. This cerebellar network oscillation has also been documented in mouse models of human conditions with complex developmental cerebellar dysfunction, such as Angelman syndrome and fetal alcohol syndrome. Recent evidence suggests a relationship between fast oscillation and cerebellar long term depression (LTD). This may have major implications for future therapeutic targeting.
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PMID:Cerebellar network plasticity: from genes to fast oscillation. 1835 74


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