Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Expansion of a polyglutamine repeat in huntingtin causes Huntington's disease (HD). Although full-length huntingtin is predominantly distributed in the cytoplasm, N-terminal fragments of huntingtin with expanded polyglutamine tracts are able to accumulate in the nucleus and kill neurons through apoptotic pathways. Transgenic mice expressing N-terminal mutant huntingtin show intranuclear huntingtin accumulation and develop progressive neurological symptoms. Inhibiting caspase-1 can prolong the survival of these HD mice. How intranuclear huntingtin is associated with caspase activation and apoptosis is unclear. Here we report that intranuclear huntingtin induces the activation of caspase-3 and the release of cytochrome c from mitochondria in cultured cells. As a result, cells expressing intranuclear huntingtin undergo apoptosis. We show that intranuclear huntingtin increases the expression of caspase-1, which may in turn activate caspase-3 and trigger apoptosis. We propose that the increased level of caspase-1 induced by intranuclear huntingtin contributes to HD-associated cell death.
Hum Mol Genet 2000 Nov 22
PMID:Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis. 1109 62

Evidence suggests overactivation of NMDA-type glutamate receptors (NMDARs) contributes to selective degeneration of medium-sized spiny striatal neurons in Huntington's disease (HD). Here we determined whether expression of huntingtin containing the polyglutamine expansion augments NMDAR-mediated excitotoxicity. HEK293 cells coexpressing mutant huntingtin (htt-138Q) and either NR1A/NR2A- or NR1A/NR2B-type NMDARs exposed to 1 mM NMDA showed a significant increase in excitotoxic cell death compared to controls (cells coexpressing htt-15Q or GFP), but the difference was larger for NR1A/NR2B. Moreover, agonist-dependent cell death showed apoptotic features for cells coexpressing htt-138Q and NR1A/NR2B, but not for cells expressing htt-138Q and NR1A/NR2A. Further, NR1A/NR2B-mediated apoptosis was not seen with coexpression of an N-terminal fragment of mutant htt. Since NR1A/NR2B is the predominant NMDAR subtype in neostriatal medium-sized spiny neurons, enhancement of NMDA-induced apoptotic death in NR1A/NR2B-expressing cells by full-length mutant htt may contribute to selective neurodegeneration in HD.
Mol Cell Neurosci 2001 Jan
PMID:Mutant huntingtin enhances excitotoxic cell death. 1116 68

Expansion of CAG repeats within the coding region of target genes is the cause of several autosomal dominant neurodegenerative diseases including Huntington's disease (HD). A hallmark of HD is the proteolytic production of N-terminal fragments of huntingtin containing polyglutamine repeats that form ubiquitinated aggregates in the nucleus and cytoplasm of the affected neurons. In this study, we used an ecdysone-inducible stable mouse neuro2a cell line that expresses truncated N-terminal huntingtin (tNhtt) with different polyglutamine length, along with mice transgenic for HD exon 1, to demonstrate that the ubiquitin-proteasome pathway is involved in the pathogenesis of HD. Proteasomal 20S core catalytic component was redistributed to the polyglutamine aggregates in both the cellular and transgenic mouse models. Proteasome inhibitor dramatically increased the rate of aggregate formation caused by tNhtt protein with 60 glutamine (60Q) repeats, but had very little influence on aggregate formation by tNhtt protein with 150Q repeats. Both normal and polyglutamine-expanded tNhtt proteins were degraded by proteasome, but the rate of degradation was inversely proportional to the repeat length. The shift of the proteasomal components from the total cellular environment to the aggregates, as well as the comparatively slower degradation of tNhtt with longer polyglutamine, decreased the proteasome's availability for degrading other key target proteins, such as p53. This altered proteasomal function was associated with disrupted mitochondrial membrane potential, released cytochrome c from mitochondria into the cytosol and activated caspase-9- and caspase-3-like proteases. These results suggest that the impaired proteasomal function plays an important role in polyglutamine protein-induced cell death.
Hum Mol Genet 2001 May 01
PMID:Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. 1133 15

The huntingtin exon 1 proteins with a polyglutamine repeat in the pathological range (51 or 83 glutamines), but not with a polyglutamine tract in the normal range (20 glutamines), form aggresome-like perinuclear inclusions in human 293 Tet-Off cells. These structures contain aggregated, ubiquitinated huntingtin exon 1 protein with a characteristic fibrillar morphology. Inclusion bodies with truncated huntingtin protein are formed at centrosomes and are surrounded by vimentin filaments. Inhibition of proteasome activity resulted in a twofold increase in the amount of ubiquitinated, SDS-resistant aggregates, indicating that inclusion bodies accumulate when the capacity of the ubiquitin-proteasome system to degrade aggregation-prone huntingtin protein is exhausted. Immunofluorescence and electron microscopy with immunogold labeling revealed that the 20S, 19S, and 11S subunits of the 26S proteasome, the molecular chaperones BiP/GRP78, Hsp70, and Hsp40, as well as the RNA-binding protein TIA-1, the potential chaperone 14-3-3, and alpha-synuclein colocalize with the perinuclear inclusions. In 293 Tet-Off cells, inclusion body formation also resulted in cell toxicity and dramatic ultrastructural changes such as indentations and disruption of the nuclear envelope. Concentration of mitochondria around the inclusions and cytoplasmic vacuolation were also observed. Together these findings support the hypothesis that the ATP-dependent ubiquitin-proteasome system is a potential target for therapeutic interventions in glutamine repeat disorders.
Mol Biol Cell 2001 May
PMID:Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation. 1135 30

Huntington's disease (HD) is caused by an expanded CAG repeat in exon 1 of the gene coding for the huntingtin protein. The cellular pathway by which this mutation induces HD remains unknown, although alterations in protein degradation are involved. To study intrinsic cellular mechanisms linked to the mutation, we examined dissociated postnatally derived cultures of striatal neurons from transgenic mice expressing exon 1 of the human HD gene carrying a CAG repeat expansion. While there was no difference in cell death between wild-type and mutant littermate-derived cultures, the mutant striatal neurons exhibited elevated cell death following a single exposure to a neurotoxic concentration of dopamine. The mutant neurons exposed to dopamine also exhibited lysosome-associated responses including induction of autophagic granules and electron-dense lysosomes. The autophagic/lysosomal compartments co-localized with high levels of oxygen radicals in living neurons, and ubiquitin. The results suggest that the combination of mutant huntingtin and a source of oxyradical stress (provided in this case by dopamine) induces autophagy and may underlie the selective cell death characteristic of HD.
Hum Mol Genet 2001 Jun 01
PMID:Expanded CAG repeats in exon 1 of the Huntington's disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. 1140 6

Huntington's disease (HD) is a progressive neurodegenerative disorder with no effective treatment. Geldanamycin is a benzoquinone ansamycin that binds to the heat shock protein Hsp90 and activates a heat shock response in mammalian cells. In this study, we show by using a filter retardation assay and immunofluorescence microscopy that treatment of mammalian cells with geldanamycin at nanomolar concentrations induces the expression of Hsp40, Hsp70 and Hsp90 and inhibits HD exon 1 protein aggregation in a dose-dependent manner. Similar results were obtained by overexpression of Hsp70 and Hsp40 in a separate cell culture model of HD. This is the first demonstration that huntingtin protein aggregation in cells can be suppressed by chemical compounds activating a specific heat shock response. These findings may provide the basis for the development of a novel pharmacotherapy for HD and related glutamine repeat disorders.
Hum Mol Genet 2001 Jun 01
PMID:Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. 1140 12

Neurodegeneration in Huntington's disease (HD) is associated with an elongated glutamine tract in the widely expressed huntingtin protein. Although the pathogenic mechanisms are still unknown, the distinct physical properties of mutant huntingtin in the brain suggest that other factors including huntingtin-interacting proteins might play a specific role. We have previously identified a DNA-binding motif in the proximal E1A promoter of adenovirus serotype 12 as responsible for E1A autoregulation. Here, we identified the p231HBP protein as a DNA-binding factor, the C-terminal portion of which has recently been characterized as the huntingtin-interacting protein HYPB of unknown function. We have determined the full-length cDNA sequence, identified several domains supporting its gene regulatory functions, and mapped the HBP231 gene to chromosome 3p21.2-p21.3. Our results provide an interesting molecular link between huntingtin and a DNA-binding factor, implicating that this interaction might result in the alteration of cellular gene expression involved in HD pathogenesis.
Mol Cell Neurosci 2001 Jul
PMID:Identification of the full-length huntingtin- interacting protein p231HBP/HYPB as a DNA-binding factor. 1146 Nov 54

Huntington's disease (HD) is a hereditary neurodegenerative condition caused by a characteristic mutation in the huntingtin (htt) gene. This gene was identified in 1993. Both the mitochondria and the nucleus play an important role in HD pathology. However, the precise molecular mechanisms remain unclear. A key strategy for understanding HD pathology is to identify signaling cascades initiated by mutant Htt that lead to neuronal cell death and dysfunction. Apoptotic stress induces greater mitochondrial depolarization in HD lymphoblasts than in control subjects. This leads to overactivation of caspase-3, which is capable of cleaving htt. Truncated forms of Htt, which are similar to the caspase-cleaved products in size, exist in the nucleus of HD patient and animal model brains. We hypothesize that caspases, which are activated by mitochondrial depolarization, play a role in producing truncated forms of Htt, which accumulate in the nucleus. Truncated forms of mutant Htt that accumulate in the nucleus are toxic to cells. There is growing evidence that truncated forms of mutant Htt in the nucleus influence gene transcription by binding to proteins such as CREB binding protein (CBP) response element binding protein binding protein, N-COR, glyceraldehyde-3-phosphate dehydrogenase, and p53. p53 regulates the transcription of various mitochondrial proteins which may underlie the mitochondrial abnormalities, especially the vulnerability to mitochondrial depolarization, seen in HD tissues. Taken together, we hypothesize a noxious signaling cascade between the mitochondria and the nucleus, initiated by mutant Htt, which may underlie HD pathology.
J Mol Med (Berl) 2001 Jul
PMID:Mechanisms for neuronal cell death and dysfunction in Huntington's disease: pathological cross-talk between the nucleus and the mitochondria? 1146 59

Fourteen neurological diseases have been associated with the expansion of trinucleotide repeat regions. These diseases have been categorized into those that give rise to the translation of toxic polyglutamine proteins and those that are untranslated. Thus far, compelling evidence has not surfaced for the inclusion of a model in which a common mechanism may participate in the pathobiology of both translated and untranslated trinucleotide diseases. In these studies we show that a double-stranded RNA-binding protein, PKR, which has previously been linked to virally-induced and stress-mediated apoptosis, preferentially binds mutant huntingtin RNA transcripts immobilized on streptavidin columns that have been incubated with human brain extracts. These studies also show, by immunodetection in tissue slices, that PKR is present in its activated form in both human Huntington autopsy material and brain tissue derived from Huntington yeast artificial chromosome transgenic mice. The increased immunolocalization of the activated kinase is more pronounced in areas most affected by the disease and, coupled with the RNA binding results, suggests a role for PKR activation in the disease process.
Hum Mol Genet 2001 Jul 15
PMID:Double-stranded RNA-dependent protein kinase, PKR, binds preferentially to Huntington's disease (HD) transcripts and is activated in HD tissue. 1146 70

The genetic basis of neurodegeneration in Huntington's disease (HD) has been identified as a (CAG)(>37) repeat expansion in a gene of unknown function. Interestingly, patients with the same expanded (CAG)(n) repeat length may have markedly different ages at onset. Based on experiences in animal models the level of expression might be one of the modifying factors. To gain insight into the regulation of the human HD gene we functionally analyzed 2266 bp of the HD gene promoter region. This region lacks a TATA and a CAAT box, is GCrich, and it has several consensus sequences for SP1, AP-2 and AP-4 binding sites. The stretch between nucleotides -49 and -198 relative to the first ATG is highly conserved between human and rodents and it harbors several potential binding sites for transcription factors. We analyzed deletion mutants fused with the chloramphenicol acetyltransferase (CAT) reporter gene in transfected, huntingtin expressing neuronal (NS20Y) and non-neuronal (CHO) cell lines. Partial deletion of the evolutionarily conserved part of the promoter significantly reduces the activity in both neuronal and non-neuronal cells indicating that the core promoter activity is located between nucleotides -221 and 4, relative to the +1 translation start site. Binding affinities of DNA-protein interactions were defined by electrophoretic mobility shift assays and the protected nucleotide positions were determined by DNase I footprinting.
Brain Res Mol Brain Res 2001 Aug 15
PMID:Functional characterization of the human Huntington's disease gene promoter. 1148 45


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