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)

Paraneoplastic opsoclonus-ataxia, a disorder of motor control, develops in breast or lung cancer patients who harbor an antibody (Ri) that recognizes their tumors and a nuclear neuronal protein of 55 kd. We have characterized a gene, Nova, encoding an antigen recognized by the Ri antibody. Nova encodes a novel, highly conserved protein, homologous to the RNA-binding protein hnRNP K, the yeast splicing protein MER1, and a motif in several retroviral proteases. Northern blot analysis detects Nova transcripts only in brain, and several alternatively spliced forms are present in brain and tumor cells. Nova expression is restricted to the ventral brain stem and spinal cord in E18 mice. Since Nova encodes a target antigen in the motor disorder paraneoplastic opsoclonus-ataxia that is expressed in the developing subcortical motor system, it is a likely participant in both the pathogenesis of paraneoplastic opsoclonus-ataxia and the developmental biology of the motor system. The homology between Nova and hnRNP K suggests that Nova regulates RNA splicing or metabolism in a specific subset of developing neurons.
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PMID:Nova, the paraneoplastic Ri antigen, is homologous to an RNA-binding protein and is specifically expressed in the developing motor system. 839 53

Many proteins contain reiterated glutamine residues, but polyglutamine of excessive length may result in human disease by conferring new properties on the protein containing it. One established property of a glutamine residue, depending on the nature of the flanking residues, is its ability to act as an amine acceptor in a transglutaminase-catalyzed reaction and to make a glutamyl-lysine cross-link with a neighboring polypeptide. To learn whether glutamine repeats can act as amine acceptors, we have made peptides with variable lengths of polyglutamine flanked by the adjacent amino acid residues in the proteins associated with spinocerebellar ataxia type 1 (SCA1), Machado-Joseph disease (SCA3), or dentato-rubral pallidoluysian atrophy (DRPLA) or those residues adjacent to the preferred cross-linking site of involucrin, or solely by arginine residues. The polyglutamine was found to confer excellent substrate properties on any soluble peptide; under optimal conditions, virtually all the glutamine residues acted as amine acceptors in the reaction with glycine ethyl-ester, and lengthening the sequence of polyglutamine increased the reactivity of each glutamine residue. In the presence of transglutaminase, peptides containing polyglutamine formed insoluble aggregates with the proteins of brain extracts and these aggregates contained glutamyl-lysine cross-links. Repeated glutamine residues exposed on the surface of a neuronal protein should form cross-linked aggregates in the presence of any transglutaminase activated by the presence of Ca2+.
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PMID:Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: relevance to diseases of the nervous system. 896 45

The presence of specific antineuronal antibodies in some patients with paraneoplastic central nervous system (CNS) disorders supports the theory that these syndromes have an autoimmune etiology. The anti-Purkinje cell antibodies (APCAs) in some patients with paraneoplastic cerebellar degeneration and ovarian or breast carcinomas stain the cytoplasm of Purkinje cells. APCAs react with several distinct neuronal protein autoantigens, including proteins featuring a "leucine zipper" sequence motif, which suggests that they function in regulating DNA transcription. Type 1 anti-neuronal nuclear antibodies (ANNA-1) associated with paraneoplastic encephalomyelitis and small-cell lung carcinoma stain the nucleus and cytoplasm of all neurons, and react with a group of 35- to 40-kd proteins in neuronal immunoblots. The protein targets of ANNA-1 belong to a family of RNA-binding proteins that probably regulate posttranscriptional processing of RNA. Type 2 anti-neuronal nuclear antibodies (ANNA-2) associated with paraneoplastic opsoclonus-ataxia and breast carcinoma also produce a panneuronal immunocytochemical staining pattern, but react with a group of higher-molecular-mass proteins (53-61 kd and 79-84 kd); these autoantigens probably also function as RNA-binding proteins. Several patients with paraneoplastic stiff-man syndrome have antibodies against a 128-kd synaptic protein. These antineuronal antibodies are highly specific (but not infallible) diagnostic markers for the presence of a neoplasm in patients who present with neurological dysfunction. The actual role of these autoantibodies in the pathogenesis of neuronal damage and clinical disease remains to be determined. Current management options for patients with CNS neurological paraneoplastic syndromes are very limited. Only a small minority of patients with paraneoplastic cerebellar degeneration or encephalomyelitis show significant neurological improvement after successful tumor treatment and/or immunosuppressive treatments, while patients with paraneoplastic opsoclonus or stiff-man syndrome have a somewhat better outlook.
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PMID:Autoimmune central nervous system paraneoplastic disorders: mechanisms, diagnosis, and therapeutic options. 896 21

A 68 year old woman with sporadic Creutzfeldt-Jakob disease is described, who neither showed characteristic EEG abnormalities nor a positive test of the neuronal protein 14-3-3 or neuron specific enolase (NSE) in CSF, despite a clinical presentation with ataxia of cerebellar type, rapidly progressive dementia, myoclonus, and marked hyperintense signal abnormalities in the deep cortical layers and the basal ganglia on T2 and diffusion weighted MRI. Moreover she showed atypical clinical features with a syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) and a peripheral sensorimotor polyneuropathy. Whether these disturbances are independent of Creutzfeldt-Jakob disease or a feature of it is discussed. It has recently been shown that in Creutzfeldt-Jakob disease different clinical and pathological phenotypes correlate with the polymorphism at codon 129 of the prion protein gene (PRNP) and the type of the protease resistant fragment that accumulates in the brain. According to the new classification at least six sporadic variants of Creutzfeldt-Jakob disease exist. The molecular genetic analysis showed heterozygosity of PRNP at codon 129 for methionine and valine and the presence of PrP(CJD) type 2 in the brain of this patient. As a new feature of changes on MRI, striking cortical changes of hyperintense signals are described in diffusion weighted as well as T2 weighted MRI that directly correlate with the histomorphological spongy degeneration of the brain in this region. In cases of rapidly progressive dementia, Creutzfeldt-Jakob disease always needs to be considered even if unusual features are present and current diagnostic criteria are not in favour of this disease.
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PMID:Clinical range and MRI in Creutzfeldt-Jakob disease with heterozygosity at codon 129 and prion protein type 2. 1051 81

Neuropathy target esterase (neurotoxic esterase, NTE), a protein thought to be involved in the production of organophosphorus compound-induced delayed neurotoxicity (OPIDN), has been postulated to be a component of endogenous neuronal protein phosphorylation systems. The purpose of this work was to test this hypothesis as well as to investigate further the role of endogenous protein phosphorylation in toxic neuropathies. White Leghorn hens were dosed with the neuropathic compounds di-1-butyl-2,2-dichlorovinyl phosphate (dibutyl dichlorvos, DBDCV), tri-o-cresyl phosphate (TOCP), or acrylamide, and regions from brain were fractionated into axolemmal, synaptosomal, and microsomal preparations. Radiolabeling of NTE or endogenously phosphorylated proteins was carried out by incubation with [14C]-DFP or gamma-[32P]-ATP, respectively. Radiolabeled proteins were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and visualized by autoradiography. Relative amounts of phosphoproteins were quantified by densitometry of the autoradiographs. Changes in endogenous phosphorylation of a protein exhibiting the characteristics of NTE were not observed in these experiments. However, levels of a [32P]-labeled 50-kDa brainstem axolemmal protein were decreased significantly on d 15, but not on d 1, 3, 7, or 10 after dosing with 2.8 mg/kg DBDCV. Clinical signs of ataxia and histopathological findings of axonal degeneration in the spinocerebellar tracts of the brainstem were evident on d 10-15, and hens were unable to perch on a horizontal wooden rod from d 12 after dosing with DBDCV. The decrease in the 50-kDa phosphoprotein was not observed on d 15 after the production of clinically evident neuropathy with either 14 daily doses of 50 mg/kg acrylamide or with a single dose of 500 mg/kg TOCP. These results suggest that NTE is not an endogenously phosphorylated protein under the conditions of these experiments. However, an effect on endogenous phosphorylation limited to a 50-kDa axolemmal protein was selectively produced by treatment with a neuropathic dose of DBDCV that was in evidence only after clinical signs and histopathological findings of axonopathy were apparent.
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PMID:Brainstem axolemmal protein phosphorylation in vitro in hens dosed with di-1-butyl-2,2-dichlorovinyl phosphate. 1070 44

The neuronal protein tyrosine phosphatases encoded by mouse gene Ptprr (PTPBR7, PTP-SL, PTPPBSgamma-42 and PTPPBSgamma-37) have been implicated in mitogen-activated protein (MAP) kinase deactivation on the basis of transfection experiments. To determine their physiological role in vivo, we generated mice that lack all PTPRR isoforms. Ptprr-/- mice were viable and fertile, and not different from wildtype littermates regarding general physiology or explorative behaviour. Highest PTPRR protein levels are in cerebellum Purkinje cells, but no overt effects of PTPRR deficiency on brain morphology, Purkinje cell number or dendritic branching were detected. However, MAP kinase phosphorylation levels were significantly altered in the PTPRR-deficient cerebellum and cerebrum homogenates. Most notably, increased phospho-ERK1/2 immunostaining density was observed in the basal portion and axon hillock of Ptprr-/- Purkinje cells. Concomitantly, Ptprr-/- mice displayed ataxia characterized by defects in fine motor coordination and balance skills. Collectively, these results establish the PTPRR proteins as physiological regulators of MAP kinase signalling cascades in neuronal tissue and demonstrate their involvement in cerebellum motor function.
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PMID:Altered MAP kinase phosphorylation and impaired motor coordination in PTPRR deficient mice. 1726 27

The actin-binding protein Kelch-like 1 (KLHL1) is a neuronal protein that belongs to the evolutionarily-conserved Kelch protein super-family. The mammalian KLHL1 is brain-specific, cytosolic and can form multimers and bind actin filaments. KLHL1's function is likely that of an actin-organizing protein, possibly modulating neurite outgrowth, the dynamic morphology of dendritic spine heads; or anchoring proteins essential for post-synaptic function, like ion channels. Targeted deletion of the KLHL1 gene in Purkinje neurons results in dendritic deficits in these neurons, abnormal gait, and progressive loss of motor coordination in mice [He Y, Zu T, Benzow KA, Orr HT, Clark HB, Koob MD (2006) Targeted deletion of a single SCA8 ataxia locus allele in mice causes abnormal gait, progressive loss of motor coordination, and Purkinje cell dendritic deficits. J Neurosci 26:9975-9982]. Here we tested the hypothesis that KLHL1 may interact and modulate voltage-gated calcium channels by assessing the interaction of the principal subunit of P/Q-type channels, alpha(1A), with KLHL1. Experiments in human embryonic kidney line HEK 293 (HEK) cells and cerebellar primary cultures revealed co-incidence of alpha(1A) and KLHL1 immunoreactivity when testing both the endogenous or epitope-tagged versions of the proteins. Similarly, co-immunoprecipitation experiments in HEK cells and brain tissue exposed the presence of KLHL1 in protein samples immunoprecipitated with FLAG-tagged or alpha(1A) antibodies. Functional studies of KLHL1 on P/Q-type current properties probed with whole-cell patch clamp revealed a significant increase in mean current density in the presence of KLHL1 (80% increase; from -13.2+/-2.0 pA/pF to -23.7+/-4.2 pA/pF, P<0.02), as well as a shift in steady state activation V(50) of -5.5 mV (from 12.8+/-1.8 mV to 7.3+/-1.0 mV, P<0.02). Our data are consistent with a modulatory effect of KLHL1 on the P/Q-type calcium channel function and suggest a possible novel role for KLHL1 in cellular excitability.
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PMID:The Kelch-like protein 1 modulates P/Q-type calcium current density. 1728 72

Neuronal protein aggregates are considered as pathological hallmarks of various human neurodegenerative diseases, including the so-called CAG-repeat disorders, such as spinocerebellar ataxia Type 6 (SCA6). Since the immunocytochemical findings of an initial post-mortem study using a specific antibody against the disease protein of SCA6 (i.e., pathologically altered alpha-1A subunit of the P/Q type voltage-dependent calcium channel, CACNA1A) have not been confirmed so far, the occurrence and central nervous system distribution of neuronal protein aggregates in SCA6 is still a matter of debate. Owing to the fact that the antibody against the pathologically altered CACNA1A is not commercially available, we decided to apply a recently generated p62 antibody on brain tissue from two clinically diagnosed and genetically confirmed SCA6 patients. Application of this p62 antibody revealed numerous cytoplasmic neuronal inclusions in the degenerated cerebellar dentate nucleus and inferior olive of both SCA6 patients studied, whereby a subset of these aggregates were also ubiquitin-immunopositive. In view of the known role of p62 in protein degradation as well as aggresome/sequestosome formation, the p62 aggregate formation observed in the present study suggests that SCA6 not only is associated with an impairment of the calcium channel function and an elongated polyglutamine stretch in CACNA1A, but also with a defective protein handling by the protein quality control system.
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PMID:The p62 antibody reveals various cytoplasmic protein aggregates in spinocerebellar ataxia type 6. 1978 49

Loss of neuronal protein stargazin (gamma(2)) is associated with recurrent epileptic seizures and ataxia in mice. Initially, due to homology to the skeletal muscle calcium channel gamma(1) subunit, stargazin and other family members (gamma(3-8)) were classified as gamma subunits of neuronal voltage-gated calcium channels (such as Ca(V)2.1-Ca(V)2.3). Here, we report that stargazin interferes with G protein modulation of Ca(V)2.2 (N-type) channels expressed in Xenopus oocytes. Stargazin counteracted the Gbetagamma-induced inhibition of Ca(V)2.2 channel currents, caused either by coexpression of the Gbetagamma dimer or by activation of a G protein-coupled receptor. Expression of high doses of Gbetagamma overcame the effects of stargazin. High affinity Gbetagamma scavenger proteins m-cbetaARK and m-phosducin produced effects similar to stargazin. The effects of stargazin and m-cbetaARK were not additive, suggesting a common mechanism of action, and generally independent of the presence of the Ca(V)beta(3) subunit. However, in some cases, coexpression of Ca(V)beta(3) blunted the modulation by stargazin. Finally, the Gbetagamma-opposing action of stargazin was not unique to Ca(V)2.2, as stargazin also inhibited the Gbetagamma-mediated activation of the G protein-activated K(+) channel. Purified cytosolic C-terminal part of stargazin bound Gbetagamma in vitro. Our results suggest that the regulation by stargazin of biophysical properties of Ca(V)2.2 are not exerted by direct modulation of the channel but via a Gbetagamma-dependent mechanism.
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PMID:Stargazin modulates neuronal voltage-dependent Ca(2+) channel Ca(v)2.2 by a Gbetagamma-dependent mechanism. 2043 86

Protein aggregation is a major pathological hallmark of many neurodegenerative disorders including polyglutamine diseases. Aggregation of the mutated form of the disease protein ataxin-3 into neuronal nuclear inclusions is well described in the polyglutamine disorder spinocerebellar ataxia type 3 (SCA3 or Machado-Joseph disease), although these inclusions are not thought to be directly pathogenic. Neuropil aggregates have not yet been described in SCA3. We performed a systematic immunohistochemical study of serial thick sections through brains of seven clinically diagnosed and genetically confirmed SCA3 patients. Using antibodies against ataxin-3, p62, ubiquitin, the polyglutamine marker 1C2 as well as TDP-43, we analyzed neuronal localization, composition and distribution of aggregates within SCA3 brains. The analysis revealed widespread axonal aggregates in fiber tracts known to undergo neurodegeneration in SCA3. Similar to neuronal nuclear inclusions, the axonal aggregates were ubiquitinated and immunopositive for the proteasome and autophagy associated shuttle protein p62, indicating involvement of neuronal protein quality control mechanisms. Rare TDP-43 positive axonal inclusions were also observed. Based on the correlation between affected fiber tracts and degenerating neuronal nuclei, we hypothesize that these novel axonal inclusions may be detrimental to axonal transport mechanisms and thereby contribute to degeneration of nerve cells in SCA3.
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PMID:Axonal inclusions in spinocerebellar ataxia type 3. 2063 90


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