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

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

In adult mice, administration of the anticonvulsive drug phenytoin caused focal swellings along the Purkinje cell axon correlated with ataxia and incoordination of movements. In our model, we used murine cerebellar slice cultures to study the influence of phenytoin on postnatal Purkinje cell axon differentiation. Almost all of our untreated cultures developed to mature-like cerebellar tissue. Immunohistochemistry with anti-calbindin-D28k or UCHTI (anti-CD3) antibodies revealed numerous Purkinje cell axons in the white matter. In the area of the deep cerebellar nuclei, immunolabelled axons formed a large axonal plexus. The few neurofilament-positive neurons in this area were densely covered with Purkinje cell axon terminals. The synaptophysin immunoreactivity revealed connections between the terminals and the neurons of the deep cerebellar nuclei. Treatment of cerebellar slice cultures with phenytoin (10-80 microM) for 10-16 days resulted in focal swellings of different size along the axon. The number of swellings increased with an increasing dosage. At concentrations of 40 microM phenytoin, Purkinje cell axons seemed to be unable to invade the deep cerebellar nuclei, but numerous aberrant, recurrent collaterals could be detected immunohistochemically with the two specific Purkinje cell antibodies. Possible cytotoxic effects after treatment, such as dendritic degeneration and a decrease in the number of immunolabelled Purkinje cells, were observed above 40 microM phenytoin. These data suggest that the response of juvenile Purkinje cells is dependent upon the dosage of the antiepileptic drug because of morphological alterations as well as a misrouting of previously established connections.
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PMID:Phenytoin alters Purkinje cell axon morphology and targeting in vitro. 965 Jul 50

Rolling mouse Nagoya (rolling: tg(rol)) is a neurologic mutant mouse exhibiting severe ataxia. Two alleles of the rolling mutation, tottering (tg) and leaner(tg(la)), have been identified as mutations in the voltage-dependent calcium channel alpha1A subunit. No specific light and electron microscopic findings have been reported for the rolling mouse cerebellum except a decreased number of granule cells, while altered Purkinje cell/parallel fiber synapses have been observed in tottering and leaner cerebella. Rolling mouse cerebella were analyzed using anti-calbindin-D immunohistochemistry and transmission electron microscopy to investigate Purkinje cell morphology and synaptic contacts between Purkinje cell dendritic spines and parallel fiber varicosities. Multiple Purkinje cell dendritic spines synapsing with single parallel fiber varicosities were frequently observed in rolling cerebella. The correlation between the presence of altered Purkinje cell synapses and ataxia in rolling mice warrants further investigation.
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PMID:Morphologic investigation of rolling mouse Nagoya (tg(rol)/tg(rol)) cerebellar Purkinje cells: an ataxic mutant, revisited. 1033 81

This study assesses the developmental expression of the Niemann-Pick type C mRNA in vivo and in vitro in rat cerebellum. NPC is an autosomal recessive neurovisceral lipid storage disease associated with an alteration in cholesterol trafficking. In the mouse model of NPC and in the early onset form of human NPC, Purkinje neurons are among the first neurological targets, suffering stunted growth during postnatal development and dying, leading to ataxia. Recently, the genes responsible for human (NPC1) and mouse (Npc1) NPC disease have been cloned. Based on a highly homologous domain, we designed primers to look for levels of Npc1 mRNA with a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) approach using cyclophilin as an internal standard. Total RNA was isolated from various postnatal developmental stages of the rat cerebellum as template for the analyses. Npc1 transcripts were observed at postnatal day 0 and at later stages of development, both in vivo and in vitro from primary cerebellar cultures. To identify the location of Npc1 inside the cerebellum, we performed immunostaining with an anti-Npc1 antibody in primary rat cerebellar cultures identifying reactive Purkinje neurons by double-labeling with the Purkinje specific marker calbindin and sub-populations of glial cells. In summary, Npc1 is expressed in rat cerebellum in vivo and in vitro and is expressed during early postnatal development as well as in the adult cerebellum. Since Npc1 is expressed at similar levels throughout development, the vulnerability of Purkinje neurons to this disease is likely to involve disruption of an interaction with other developmentally-regulated proteins.
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PMID:Expression of Niemann-Pick type C transcript in rodent cerebellum in vivo and in vitro. 1048 98

Arylsulfatase A (ASA)-deficient (-/-) mice and ASA(+/+) controls were constructed as a transgenic model for the lysosomal storage disease, metachromatic leukodystrophy (MLD). One-year-old ASA(-/-) mice showed impaired rotarod performance and altered walking pattern characterized by a shorter pace, later evolving into more severe ataxia with tremor in 2-year-old mice. Examination of cerebellar histology showed that 2-year-old ASA(-/-) mice have lost most of the calbindin immunoreactivity from their Purkinje cell dendrites and show simplified dendritic architecture. Additionally, ASA-deficient mice lost a substantial proportion of their Purkinje cells. Recordings of unitary potentials and stimulation of climbing fibers on cerebellar slices from 2-year-old mice indicated that, although the main cerebellar synapses seem to be present and functioning physiologically, the climbing fibers of ASA-deficient mice may have enhanced effects on Purkinje cell activity. It is concluded that ambulatory dysfunctions in ASA(-/-) mice might be explained by an imbalance in the consequences of climbing fiber signals upon Purkinje cell activity due to selective neurodegeneration within the cerebellum.
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PMID:Neuromotor alterations and cerebellar deficits in aged arylsulfatase A-deficient transgenic mice. 1050 24

This study reports on the mode of inheritance of the shaker mutation and the development of an inbred strain of the shaker rat mutation from Sprague Dawley outbred stock onto a Wistar Furth background. Neuroanatomical and behavioral expression of the affected phenotype, through seven generations of backcross and intercross breeding, has confirmed the mode of inheritance to be X-linked. Behaviorally, affected mutants present with a wide-based ataxic gait and whole body tremor. In affected mutants calbindin immunostaining for surviving cerebellar Purkinje cells revealed widespread degeneration in the anterior lobe and in limited areas of the posterior lobe. Fast Fourier transform analysis of the tremor revealed a frequency of 3-5 Hz. As predicted by X-linked inheritance, female descendants of an affected male are carriers for the genotype and the phenotype is expressed in one-half of her male offspring. There was spatially random and limited degeneration of Purkinje cells in carrier females, but they did not display overt clinical signs of ataxia and tremor. These data provide further support for using the shaker mutant rat as an animal model for studies of mechanisms underlying human heredodegenerative diseases.
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PMID:X-linked transmission of the shaker mutation in rats with hereditary Purkinje cell degeneration and ataxia. 1070 77

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


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