Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0004134 (ataxia)
15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The expansion of an unstable CAG repeat causes spinocerebellar ataxia type 1 (SCA1) and several other neurodegenerative diseases. How polyglutamine expansions render the resulting proteins toxic to neurons, however, remains elusive. Hypothesizing that long polyglutamine tracts alter gene expression, we found certain neuronal genes involved in signal transduction and calcium homeostasis sequentially downregulated in SCA1 mice. These genes were abundant in Purkinje cells, the primary site of SCA1 pathogenesis; moreover, their downregulation was mediated by expanded ataxin-1 and occurred before detectable pathology. Similar downregulation occurred in SCA1 human tissues. Altered gene expression may be the earliest mediator of polyglutamine toxicity.
...
PMID:Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. 1064 62

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.
...
PMID:Relationship between ataxin-1 nuclear inclusions and Purkinje cell specific proteins in SCA-1 transgenic mice. 1072 95

To elucidate the pathophysiology of spinocerebellar ataxia type 1 (SCA1) and to evaluate repeat length instability in the context of the mouse Sca1 gene, we generated knock-in mice by inserting an expanded tract of 78 CAG repeats into the mouse Sca1 locus. Mice heterozygous for the CAG expansion show intergenerational repeat instability (+2 to -6) at a much higher frequency in maternal transmission than in paternal transmission. The majority of changes transmitted through the female germline were small contractions, as in humans, whereas small expansions occurred more frequently in paternal transmission. The frequency of intergenerational changes was age dependent for both paternal and maternal transmissions. Mice homozygous for mutant ataxin-1 on a C57BL/6J-129/SvEv mixed background performed significantly less well on the rotating rod than did wild-type littermates at 9 months of age, although they were not ataxic by cage behavior. Histological examination of brain tissue from mutant mice up to 18 months of age revealed none of the neuropathological changes observed in other transgenic models overexpressing expanded polyglutamine tracts. These data suggest that, even with 78 glutamines, prolonged exposure to mutant ataxin-1 at endogenous levels is necessary to produce a neurological phenotype reminiscent of human SCA1. Pathogenesis is thus a function of polyglutamine length, protein levels and duration of neuronal exposure to the mutant protein.
...
PMID:Repeat instability and motor incoordination in mice with a targeted expanded CAG repeat in the Sca1 locus. 1074 85

Expansion of a polyglutamine tract within ataxin-1 causes spinocerebellar ataxia type 1 (SCA1). In this study, we used the yeast two-hybrid system to identify an ataxin-1-interacting protein, A1Up. A1Up localized to the nucleus and cytoplasm of transfected COS-1 cells. In the nucleus, A1Up co-localized with mutant ataxin-1, further demonstrating that A1Up interacts with ataxin-1. Expression analyses demonstrated that A1U mRNA is widely expressed as an approximately 4.0 kb transcript and is present in Purkinje cells, the primary site of SCA1 cerebellar pathology. Sequence comparisons revealed that A1Up contains an N-terminal ubiquitin-like (UbL) region, placing it within a large family of similar proteins. In addition, A1Up has substantial homology to human Chap1/Dsk2, a protein that binds the ATPase domain of the HSP70-like Stch protein. These results suggest that A1Up may link ataxin-1 with the chaperone and ubiquitin-proteasome pathways. In addition, these data support the concept that ataxin-1 may function in the formation and regulation of multimeric protein complexes within the nucleus.
...
PMID:Identification and characterization of an ataxin-1-interacting protein: A1Up, a ubiquitin-like nuclear protein. 1100 34

It is not known why expression of a protein with an expanded polyglutamine region is pathogenic in spinocerebellar ataxia, Huntington's disease and several other neurodegenerative diseases. Dietary supplementation with creatine improves survival and motor performance and delays neuronal atrophy in the R6/2 transgenic mouse model of Huntington's disease. These effects may be due to improved energy and calcium homeostasis, enhanced presynaptic glutamate uptake, or protection of mitochondria from the mitochondrial permeability transition. We tested the effects of a 2% creatine-supplemented diet and treatment with taurine-conjugated ursodeoxycholic acid, a bile constituent that can inhibit the mitochondrial permeability transition, on ataxia and Purkinje cell survival in a transgenic model of spinocerebellar ataxia type 1. After 24 weeks, transgenic mice on the 2% creatine diet had cerebellar phosphocreatine levels that were 72.5% of wildtype controls, compared to 26.8% in transgenic mice fed a control diet. The creatine diet resulted in maintenance of Purkinje cell numbers in these transgenic mice at levels comparable to wildtype controls, while transgenic mice fed a control diet lost over 25% of their Purkinje cell population. Nevertheless, the ataxic phenotype was neither improved nor delayed. Repeated s.c. ursodeoxycholic acid injections markedly elevated ursodeoxycholic acid levels in the brain without adverse effects, but provided no improvement in phenotype or cell survival in spinocerebellar ataxia type 1 mice. These results demonstrate that preserving neurons from degeneration is insufficient to prevent a behavioral phenotype in this transgenic model of polyglutamine disease. In addition, we suggest that the means by which creatine mitigates against the neurodegenerative effects of an ataxin-1 protein containing an expanded polyglutamine region is through mechanisms other than stabilization of mitochondrial membranes.
...
PMID:Creatine-supplemented diet extends Purkinje cell survival in spinocerebellar ataxia type 1 transgenic mice but does not prevent the ataxic phenotype. 1127 90

The androgen receptor is a member of the nuclear receptor superfamily, and regulates gene expression in response to the steroid hormones testosterone and dihydrotestosterone. Mutations in the receptor have been correlated with a diverse range of clinical conditions, including androgen insensitivity, prostate cancer and spinal bulbar muscular atrophy, a neuromuscular degenerative condition. The latter is caused by expansion of a polyglutamine repeat within the N-terminal domain of the receptor. Thus the androgen receptor is one of a growing number of neurodegenerative disease-associated proteins, including huntingtin (Huntington's disease), ataxin-1 (spinocerebellar ataxia, type 1) and ataxin-3 (spinocerebellar ataxia, type 3), which show expansion of CAG triplet repeats. Although widely studied, the functions of huntingtin, ataxin-1 and ataxin-3 remain unknown. The androgen receptor, which has a well-recognized function in gene regulation, provides a unique opportunity to investigate the functional significance of poly(amino acid) repeats in normal and disease states.
...
PMID:Structural and functional alterations in the androgen receptor in spinal bulbar muscular atrophy. 1135 58

Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expression of mutant ataxin-1 that contains an expanded polyglutamine tract. Overexpression of mutant ataxin-1 in Purkinje cells of transgenic mice results in a progressive ataxia and Purkinje cell pathology that are very similar to those seen in SCA1 patients. Two prominent aspects of pathology in the SCA1 mice are the presence of cytoplasmic vacuoles and dendritic atrophy. We found that the vacuoles in Purkinje cells seem to originate as large invaginations of the outer cell membrane. The cytoplasmic vacuoles contained proteins from the somatodendritic membrane, including mGluR1, GluRDelta1/Delta2, GluR2/3, and protein kinase C (PKC) gamma. Further examination of PKCgamma revealed that its sequestration into cytoplasmic vacuoles was accompanied by concurrent loss of PKCgamma localization at the Purkinje cell dendritic membrane and decreased detection of PKCgamma by Western blot analysis. In addition, the vacuoles were immunoreactive for components of the ubiquitin/proteasome degradative pathway. These findings present a link between vacuole formation and loss of dendrites in Purkinje cells of SCA1 mice and indicate that altered somatodendritic membrane trafficking and loss of proteins including PKCgamma, are a part of the neuronal dysfunction in SCA1 transgenic mice.
...
PMID:Altered trafficking of membrane proteins in purkinje cells of SCA1 transgenic mice. 1154 83

The expansion of a polyglutamine tract in the ataxin-1 protein beyond a critical threshold causes spinocerebellar ataxia type 1 (SCA1). To investigate the mechanism of neuronal degeneration in SCA1, we analyzed the phenotype of an SCA1 transgenic mouse model in the absence of p53, an important regulator of cell death. p53 deficiency did not affect the early features of SCA1 mice such as impaired motor coordination and ataxin-1 nuclear inclusion formation but caused a notable reduction in later pathological features, including Purkinje cell heterotopia, dendritic thinning, and molecular layer shrinkage. To determine if this protective effect was mediated by an anti-apoptotic property of p53 deficiency, we looked for apoptosis in SCA1 mice but failed to detect any evidence of it even in the presence of p53. We propose that p53 acts after the initial pathogenic events in SCA1 to promote the progression of neuronal degeneration in SCA1 mice, but this activity may be unrelated to apoptosis.
...
PMID:Reduction of Purkinje cell pathology in SCA1 transgenic mice by p53 deletion. 1174 93

CAG repeat expansions with loss of CAT interruptions in the coding region of the ataxin-1 gene are associated with spinocerebellar ataxia type 1 (SCA1). For molecular genetic diagnosis it is necessary to define the limits of normal and pathological size ranges. In most studies, normal alleles as measured by PCR range from 6-39 units with interruptions of 1-3 CAT trinucleotides that are thought to be involved in the stability of the trinucleotide stretch during DNA replication. Expanded alleles have been reported to carry 39-81 CAG trinucleotides without stabilising CAT interruptions. To evaluate the limits between normal and disease size ranges we analysed the repeat length and composition of the SCA1 gene in 15 individuals with alleles ranging from 36 and 41 triplets for genotype-phenotype correlation studies. We found the 39 trinucleotide-allele to be either interrupted by CAT repeats or formed by a pure CAG stretch. The clinical features of individuals carrying 39 uninterrupted CAG repeats did not differ from the SCA1 phenotype in general with dysphagia, pale discs, pyramidal signs and cerebellar tremor being more frequent as compared to other SCA genotypes. In contrast, the interrupted 39 trinucleotide-allele is not correlated with the SCA1 phenotype.
...
PMID:Spinocerebellar ataxia type 1 (SCA1): phenotype-genotype correlation studies in intermediate alleles. 1197 25

Spinocerebellar ataxia type 1 (SCA1) belongs to a family of polyglutamine induced neurodegenerative disorders. Transgenic mice that overexpress a mutant allele of the SCA1 gene develop a progressive ataxia and Purkinje cell pathology. In this report, the pathological importance of a segment of ataxin-1 previously shown to be important for protein-protein interactions was examined. While the absence of a 122 amino acid segment from the protein-protein interaction region of ataxin-1 did not effect the initiation of disease, its absence substantially suppressed the progression of disease in SCA1 transgenic mice. Thus, these data suggest that this region of ataxin-1 has a role in disease progression. Furthermore, these results provide evidence that ataxin-1-induced disease initiation and disease progression involve distinct molecular events.
...
PMID:Amino acids in a region of ataxin-1 outside of the polyglutamine tract influence the course of disease in SCA1 transgenic mice. 1202 14


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---