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)

Dynamic mutations in human genes result from unstable trinucleotide repeats which are expanded within the genome. These expansions of trinucleotide repeats have been shown to be the etiological factors in various neuropsychiatric diseases and other genetic disorders. This hypothesis is supported by various independent studies showing large expansion of trimeric repeats, such as CAG/CTG/CCG/CGG/AAG, in patient DNA samples. These repeats are also identified in other disease loci not clearly related to particular diseases, which indicates that such expansions are one of the general forms of evolution occurring throughout the human genome. The trinucleotide repeat expansions occur during meiosis and are generally irreversible. Accumulation of these repeats over generations eventually ends in a deficiency of replication. There is evidence that certain ethnic groups in the human population have predispositions for expanded repeats related to neuropsychiatric diseases. It is likely that racial/ethnic differences reflect variations, which suggests the possibility of an underlying complex biological process. The present review highlights the importance of repeat expansions in some neuropsychiatric diseases, such as spinal and bulbular atrophy (SBMA), spinocerebellar ataxia (SCA), Huntington's disease (HD), schizophrenia, myotonic dystrophy (DM) and fragile-X syndrome.
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PMID:DNA trinucleotide repeat expansion in neuropsychiatric patients. 1296 Sep 39

A mutation of the DYT1 gene, which codes for torsinA, has been identified as a cause of autosomal dominantly inherited dystonia. The function of torsinA is not yet known, but it is found throughout the central nervous system and has been identified in Lewy bodies in Parkinson's disease. We examined cases of Huntington's disease, spinocerebellar ataxia type III, and Huntington's disease-like 2 using antibodies to torsinA, and found that ubiquitinated, intranuclear neuronal inclusions were torsinA-immunoreactive, possibly indicating a role for torsinA in protein degradation.
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PMID:TorsinA immunoreactivity in inclusion bodies in trinucleotide repeat diseases. 1450 72

Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive cerebellar ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identified recently. We studied a large series of 158 families with non-Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8 +/- 4.8 years (range 2-18 years). Cerebellar ataxia with cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with 'slow saccades'. We emphasize the phenotypic variability over the course of the disease. Cerebellar ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich's ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington's disease.
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PMID:Cerebellar ataxia with oculomotor apraxia type 1: clinical and genetic studies. 1450 70

The relevance of gluten sensitivity in sporadic and hereditary ataxia pathogenesis is unclear. The authors found high antigliadin antibody titers in 23 of 52 (44%) patients with Huntington's disease (HD), suggesting a previously unrecognized association between HD and gluten sensitivity. The results further question "gluten ataxia" as a distinct disease entity and raise the possibility that antigliadin antibodies in ataxia and other neurodegenerative diseases may be an epiphenomenon, the mechanisms of which remain to be investigated.
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PMID:Antigliadin antibodies in Huntington's disease. 1532 72

Childhood ataxia with central nervous system hypomyelination (CACH), or vanishing white matter leukoencephalopathy (VWM), is a fatal brain disorder caused by mutations in eukaryotic initiation factor 2B (eIF2B). eIF2B is essential for protein synthesis and regulates translation in response to cellular stresses. We performed mutagenesis to introduce changes equivalent to 12 human CACH/VWM mutations in three subunits of the equivalent factor from yeast (Saccharomyces cerevisiae) and analyzed effects on cell growth, translation, and gene expression in response to stresses. None of the mutations is lethal or temperature sensitive, but almost all confer some defect in eIF2B function significant enough to alter growth or gene expression under normal or stress conditions. Biochemical analyses indicate that mutations analyzed in eIF2Balpha and -epsilon reduce the steady-state level of the affected subunit, while the most severe mutant tested, eIF2Bbeta(V341D) (human eIF2B(betaV316D)), forms complexes with reduced stability and lower eIF2B activity. eIF2Bdelta is excluded from eIF2Bbeta(V341D) complexes. eIF2B(betav341D) function can be rescued by overexpression of eIF2Bdelta alone. Our findings imply CACH/VWM mutations do not specifically impair responses to eIF2 phosphorylation, but instead cause protein structure defects that impair eIF2B activity. Altered protein folding is characteristic of other diseases, including cystic fibrosis and neurodegenerative disorders such as Huntington, Alzheimer's, and prion diseases.
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PMID:Mutations causing childhood ataxia with central nervous system hypomyelination reduce eukaryotic initiation factor 2B complex formation and activity. 1499 75

A common feature of many neurodegenerative diseases, including Alzheimer's and Parkinsons's disease, the prion disorders, and the CAG repeat polyglutamine (polyQ) diseases, is the occurrence of protein aggregates within or outside of nerve cells. Molecular chaperones such as heat shock proteins (HSPs) have been proposed to play a critical role in preventing the accumulation of misfolded proteins that lead to the deposition of aggregates during pathology. This article focuses on the role of HSPs during polyQ pathologies, which include Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral and pallidoluysian atrophy, and several forms of spinocerebellar ataxia. Recently, unifying mechanisms that are involved during polyQ disease have emerged, such as abnormal transcription, impaired degradation systems, and interference of a polyQ expansion with neuronal survival and death-signaling pathways like the activation of caspases and kinases. This article reviews recent studies that point to the involvement of these mechanisms during polyQ pathology and discusses how HSPs can interfere with such processes by paying special attention to HSPs as modulators of survival and death-signaling pathways.
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PMID:Role of heat shock proteins during polyglutamine neurodegeneration: mechanisms and hypothesis. 1512 94

Polyglutamine diseases are characterized by neuronal intranuclear inclusions (NIIs) of expanded polyglutamine proteins, indicating the failure of protein degradation. UBB(+1), an aberrant form of ubiquitin, is a substrate and inhibitor of the proteasome, and was previously reported to accumulate in Alzheimer disease and other tauopathies. Here, we show accumulation of UBB(+1) in the NIIs and the cytoplasm of neurons in Huntington disease and spinocerebellar ataxia type-3, indicating inhibition of the proteasome by polyglutamine proteins in human brain. We found that UBB(+1) not only increased aggregate formation of expanded polyglutamines in neuronally differentiated cell lines, but also had a synergistic effect on apoptotic cell death due to expanded polyglutamine proteins. These findings implicate UBB(+1) as an aggravating factor in polyglutamine-induced neurodegeneration, and clearly identify an important role for the ubiquitin-proteasome system in polyglutamine diseases.
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PMID:Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases. 1519 95

To date, nine progressive neurodegenerative diseases are caused by expansion of the CAG repeat coding for polyglutamine, including Huntington's disease and several forms of spinocerebellar ataxia. Expanded polyglutamine causes dominant toxic gain-of-function related to its ability to aggregate. Polyglutamine aggregates inhibit the proteasome, suggesting that reduced degradation of misfolded proteins might contribute to polyglutamine toxicity. Moreover, several observations indicate that soluble proteins harboring expanded polyglutamine display altered turnover. To examine whether soluble polyglutamine interfered with proteasome-mediated degradation, we analyzed degradation of model proteasome substrates carrying either 103 or 25 glutamines in transfected cells. Expanded and normal size polyglutamine were degraded to completion and with similar efficiency. Moreover, targeting of expanded polyglutamine for proteasome-mediated degradation did not compromise proteasome activity. Thus, we propose that polyglutamine-containing disease proteins can be readily digested by the proteasome if they carried a degradation signal.
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PMID:Proteasome degrades soluble expanded polyglutamine completely and efficiently. 1520 77

To elucidate the etiology of chorea, we performed gene diagnoses of 79 consecutive cases of the disease (34 males, 45 females; age 15-79 years), which include 39 familial cases (37 pedigrees) and 40 sporadic cases, from 1997 to 2002, after their informed consent was obtained. We extracted genomic DNA from peripheral white blood cells, and performed genetic tests for Huntington disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), Huntington disease like 1 (HDL1), HDL2 and spinocerebellar ataxia type 17 (SCA17). We found 37 cases (36 pedigrees) of HD, seven cases (seven pedigrees) of DRPLA. No cases of HDL1, HDL2 and SCA17 were found. We also found three cases (two pedigrees) presenting an autosomal dominant trait with an unknown origin, and two cases whose parents were consanguineously related. Therefore, further genetic heterogeneity is expected in the cases of chorea in Japan.
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PMID:[Gene diagnosis of patients with chorea]. 1523 65

The dominant polyglutamine expansion diseases, which include spinocerebellar ataxia type 1 (SCA1) and Huntington disease, are progressive, untreatable, neurodegenerative disorders. In inducible mouse models of SCA1 and Huntington disease, repression of mutant allele expression improves disease phenotypes. Thus, therapies designed to inhibit expression of the mutant gene would be beneficial. Here we evaluate the ability of RNA interference (RNAi) to inhibit polyglutamine-induced neurodegeneration caused by mutant ataxin-1 in a mouse model of SCA1. Upon intracerebellar injection, recombinant adeno-associated virus (AAV) vectors expressing short hairpin RNAs profoundly improved motor coordination, restored cerebellar morphology and resolved characteristic ataxin-1 inclusions in Purkinje cells of SCA1 mice. Our data demonstrate in vivo the potential use of RNAi as therapy for dominant neurodegenerative disease.
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PMID:RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. 1528 70


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