Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q9NRP7 (fused)
 58,367 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ataxia-telangiectasia (A-T) is inherited as an monogenetic autosomal recessive disease. Ataxia appears around 1 year of age and progresses until the patient becomes wheelchair-bound, usually by age 10. This progress correlates with deterioration of Purkinje cells in the cerebellum. Sinopulmonary infections are common in patients from some countries but not others. One-third of the patients develop a neoplasm, usually lymphoid, sometime during their shortened lives. Conventional doses of radiation therapy for such cancers are contraindicated since A-T patients are hypersensitive to ionizing radiation. Five complementation groups have been described, based on correction of radioresistant DNA synthesis of fused fibroblasts from pairs of patients. Chromosomal translocations are found in 5-10% of peripheral T cells from most patients and the translocation breakpoints involve sites of normal somatic DNA rearrangement. Thus, the A-T gene(s) effects several cell lineages, suggesting that it is a "housekeeping" gene. Other speculations on "candidate genes" are considered. Recent progress localizing A-T to chromosome 11q23 is reviewed.
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PMID:Speculations on the ataxia-telangiectasia defect. 171 44

The anticonvulsant valproic acid (VPA), or 2-propylpentanoic acid, is a short-chain aliphatic acid that is teratogenic in humans and rodents. VPA and 14 related chemicals were screened for developmental toxicity using the Chernoff/Kavlock assay. Test agents, in corn oil, were administered by gavage to Sprague-Dawley rats once daily during organogenesis. The dams were allowed to deliver and the pups were examined postnatally. Segment II studies were also conducted using VPA and pentanoic acid in rats and with VPA in CD-1 mice. In both mice and rats, VPA caused transient maternal ataxia and developmental defects of the digits and, especially, the axial skeleton. Exencephaly, however, was seen only in mice. The screening protocol was effective in prioritizing agents within this class of compounds for more definitive developmental toxicity testing. All congeners tested induced maternal respiratory effects and six compounds caused motor depression. Only 2-ethylhexanoic (2EH) and 2-propylhexanoic (2PH) acid caused dramatic VPA-like effects on rat development (including mortality, extra presacral vertebrae, fused ribs, and delayed parturition), confirming the strict structural requirements for developmental toxicity previously reported for acute exposure in mice. The incorporation of skeletal examinations in the Chernoff/Kavlock assay enabled the detection of the sole developmental effect (increased incidence of lumbar ribs) of 2-butylhexanoic acid. VPA, 2EH, and 2PH were among the compounds that caused maternal motor depression. These data, consistent with previous reports, indicate a broader specificity for activity in the adult nervous system than that in the developing system and suggest differing mechanisms for the two effects.
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PMID:Developmental toxicity and structure-activity relationships of aliphatic acids, including dose-response assessment of valproic acid in mice and rats. 800 77

Eight diseases, exemplified by Huntington's disease and spinocerebellar ataxia type 1, are caused by CAG-repeat expansion mutations. The CAG repeats are translated into expanded polyglutamine tracts, which are associated with deleterious novel functions. While these diseases are characterized by intraneuronal aggregate formation, it is unclear whether the aggregates cause disease. We have addressed this debate by generating intracellular aggregates with green fluorescent protein (GFP) fused to 19-37 alanines. No aggregates were seen in cells expressing native GFP or GFP fused to seven alanines. Aggregate-containing cells expressing GFP fused to 19-37 polyalanines show high rates of nuclear fragmentation compared with cells expressing the same constructs without aggregates, or cells expressing GFP fused to seven alanines. This suggests an association between aggregate formation and cell death.
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PMID:Intracellular green fluorescent protein-polyalanine aggregates are associated with cell death. 1079 8

Rhombencephalosynapsis (RS) is a relatively rare developmental disorder of the cerebellum in which the cerebellar hemispheres are fused across the midline without being separated by a cleft or the vermis. The condition may be associated with hydrocephalus and other intracranial and extracranial abnormalities. The authors report on the case of a symptomatic adult who was successfully treated with suboccipital decompression and duraplasty. A 39-year-old woman presented with intractable pain radiating from the thoracolumbar column to the occiput. A general examination yielded normal findings and a neurological examination revealed only subtle ataxia of tandem gait. The patient underwent magnetic resonance (MR) imaging, the results of which revealed an absent cerebellar vermis with fusion of the cerebellum and mild hydrocephalus. A cine-MR image obtained to evaluate her cerebrospinal fluid flow (CSF) revealed attenuated flow in the posterior fossa and cerebral aqueduct. Preoperative intracranial pressure (ICP) monitoring demonstrated no elevation of ICP (mean 4.3 mm Hg). The patient consented to undergo suboccipital craniectomy and duraplasty. Despite an increase in postoperative ICP (mean 10.77 mm Hg; difference from preoperative level according to a t-test, p = 0.002), the patient experienced symptomatic relief, which has persisted for 3 years. One year postoperatively, a cine-MR image was obtained, which revealed improvement in the patient's CSF dynamics. The authors conclude that, although RS may cause altered flow in the adult, their patient has experienced symptomatic relief, suggesting that her pain was related to local pressure in the posterior fossa.
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PMID:Adult rhombencephalosynapsis. Case report. 1093 20

Atlanto-occipital fusion in a Japanese Brown calf was examined morphologically, paying special attention to skeletal changes. At the craniovertebral junction, the basal occipital bone fused to the cranial extremity of the ventral arch of the atlas with the rudiment of the atlantal centrum. The dens was not formed at the axis. These changes suggest that a hypocentrum and a centrum of the atlas derived from the first cervical sclerotome had failed to separate the occipital base from the proatlantal sclerotome including the apical element of the dens. Although a developmental disturbance at the cervical and thoracic vertebrae was also associated, critical neurological signs such as ataxia and paralysis were absent.
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PMID:Skeletal aspects of the atlanto-occipital fusion in a Japanese brown calf. 1178 14

The restriction endonuclease SmaI has been used for the diagnosis of neurogenic muscle weakness, ataxia and retinitis pigmentosa disease or Leigh's disease, caused by the Mt8993T-->G mutation which results in a Leu156Arg replacement that blocks proton translocation activity of subunit a of F(0)F(1)-ATPase. Our ultimate goal is to apply SmaI to gene therapy for this disease, because the mutant mitochondrial DNA (mtDNA) coexists with the wild-type mtDNA (heteroplasmy), and because only the mutant mtDNA, but not the wild-type mtDNA, is selectively restricted by the enzyme. For this purpose, we transiently expressed the SmaI gene fused to a mitochondrial targeting sequence in cybrids carrying the mutant mtDNA. Here, we demonstrate that mitochondria targeted by the SmaI enzyme showed specific elimination of the mutant mtDNA. This elimination was followed with repopulation by the wild-type mtDNA, resulting in restoration of both the normal intracellular ATP level and normal mitochondrial membrane potential. Furthermore, in vivo electroporation of the plasmids expressing mitochondrion-targeted EcoRI induced a decrease in cytochrome c oxidase activity in hamster skeletal muscles while causing no degenerative changes in nuclei. Delivery of restriction enzymes into mitochondria is a novel strategy for gene therapy of a special form of mitochondrial diseases.
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PMID:Gene therapy for mitochondrial disease by delivering restriction endonuclease SmaI into mitochondria. 1237 91

Heterotrimeric serine/threonine protein phosphatase 2A (PP2A) consists of scaffolding (A), catalytic (C), and variable (B, B', and B'') subunits. Variable subunits dictate subcellular localization and substrate specificity of the PP2A holoenzyme. The Bbeta regulatory subunit gene is mutated in spinocerebellar ataxia type 12, and one of its splice variants, Bbeta2, targets PP2A to mitochondria to promote apoptosis in PC12 cells (Dagda, R. K., Zaucha, J. A., Wadzinski, B. E., and Strack, S. (2003) J. Biol. Chem. 278, 24976-24985). Here, we report that Bbeta2 is localized to the outer mitochondrial membrane by a novel mechanism, combining a cryptic mitochondrial import signal with a structural arrest domain. Scanning mutagenesis demonstrates that basic and hydrophobic residues mediate mitochondrial association and the proapoptotic activity of Bbeta2. When fused to green fluorescent protein, the N terminus of Bbeta2 acts as a cleavable mitochondrial import signal. Surprisingly, full-length Bbeta2 is not detectably cleaved and is retained at the outer mitochondrial membrane, even though it interacts with the TOM22 import receptor, as shown by luciferase complementation in intact cells. Mutations that open the C-terminal beta-propeller of Bbeta2 facilitate mitochondrial import, indicating that this rigid fold acts as a stop-transfer domain by resisting the partial unfolding step prerequisite for matrix translocation. Because hybrids of prototypical import and beta-propeller domains recapitulate this behavior, we predict the existence of other similarly localized proteins and a selection against highly stable protein folds in the mitochondrial matrix. This unfolding-resistant targeting to the mitochondrial translocase is necessary but not sufficient for the proapoptotic activity of Bbeta2, which also requires association with the rest of the PP2A holoenzyme.
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PMID:Unfolding-resistant translocase targeting: a novel mechanism for outer mitochondrial membrane localization exemplified by the Bbeta2 regulatory subunit of protein phosphatase 2A. 1592 82

Niemann Pick type C (NPC) disease is an autosomal recessive disorder characterized by abnormal cholesterol metabolism and accumulation in lysosomal and endosomal compartments. Although peripheral organs are affected, the progressive neurodegeneration in the brain is typically most deleterious, leading to dystonia, ataxia, seizures, and premature death. Although the two genes underlying this disorder in humans and mouse models of the disease have been identified (NPC1 in 95% and NPC2/HE1 in 5% of human cases), their cellular roles have not Been fully defined, and there is currently no effective treatment for this disorder. To help address these issues, we constructed a recombinant adenovirus, Ad(NPC1-GFP), which contains a cDNA encoding a mouse NPC1 protein with a green fluorescent protein (GFP) fused to its C-terminus. Fluorescence microscopy and cholesterol trafficking assays demonstrate that the GFP-tagged NPC1 protein is functional and detectable in cells from different species (hamster, mouse, human) and of different types (ovary-derived cells, fibroblasts, astrocytes, neurons from peripheral and central nervous systems) in vitro. Combined with results from time-lapse microscopy and in vivo brain injections, our findings suggest that this adenovirus offers advantages for expressing NPC1 and analyzing its cellular localization, movement, functional properties, and beneficial effects in vitro and in vivo.
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PMID:Adenovirus expressing an NPC1-GFP fusion gene corrects neuronal and nonneuronal defects associated with Niemann pick type C disease. 1601 97

Mesenchymal stem cells have been proven to be potentially effective in the treatment of a large variety of diseases, including neurodegenerative disorders. Of these, cerebellar ataxia is a group of disorders characterized by the degeneration of the cerebellum, particularly the Purkinje cells, responsible for motor coordination and control of the motor functions. To analyze the possibility of using bone marrow-derived mesenchymal stem cells in treating ataxia, we transplanted these cells in the cerebellum of newborn Lurcher mutant mice, a very aggressive mouse model characterized by the selective early post-natal death of Purkinje cells in the cerebellum. Two months after the surgical procedure, the treated mice presented significant improvements in the motor behavior tests performed. Histological analysis of the cerebellum indicated that the donor cells had migrated throughout the cerebellum, as well as a significant increase in the number of Purkinje cells. Many grafted stem cells were located adjacent to the Purkinje cell layer, and expressed BDNF, NT-3 or GDNF, neurotrophic factors implicated in Purkinje cell survival. Also, a small percentage of the grafted stem cells had fused with Purkinje cells. Thus, we have shown that mesenchymal stem cells are capable of integrating into the central nervous system, migrate towards the areas where neurodegenerative processes are occurring, and rescue the degenerating cells through cell trophic effects. This is an adequate and feasible model that could be translated into a therapeutic approach for clinical assays in neurodegenerative diseases.
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PMID:Mesenchymal stem cells rescue Purkinje cells and improve motor functions in a mouse model of cerebellar ataxia. 2063 77

The presence of aggregates of abnormally expanded polyglutamine (polyQ)-containing proteins are a pathological hallmark of a number of neurodegenerative diseases including Huntington's disease (HD) and spinocerebellar ataxia-3 (SCA3). Previous studies in cellular, Drosophila, and mouse models of HD and SCA have shown that neurodegeneration can be prevented by manipulations that inhibit polyQ aggregation. We have shown that the UL97 kinase of the human cytomegalovirus (HCMV) prevents aggregation of the pp71 and pp65 viral tegument proteins. To explore whether UL97 may act as a general antiaggregation factor, we examined whether UL97 prevents aggregation of cellular non-polyQ and polyQ proteins. We report that UL97 prevents the deposition of aggregates of two non-polyQ proteins: a protein chimera (GFP170*) composed of the green fluorescent protein and a fragment of the Golgi Complex protein (GCP-170) and a chimera composed of the red fluorescent protein (RFP) fused to the Werner syndrome protein (WRN), a RecQ helicase and exonuclease involved in DNA repair. Furthermore, we show that UL97 inhibits aggregate deposition in cellular models of HD and SCA3. UL97 prevents the deposition of aggregates of the mutant huntingtin exon 1 containing 82 glutamine repeats (HttExon1-Q82) or full length ataxin-3 containing a 72 polyQ track (AT3-72Q). The kinase activity of UL97 appears critical, as the kinase-dead UL97 mutant (K335M) fails to prevent aggregate formation. We further show that UL97 disrupts nuclear PML bodies and decreases p53-mediated transcription. The universality of the antiaggregation effect of UL97 suggests that UL97 targets a key cellular factor that regulates cellular aggregation mechanisms. Our results identify UL97 as a novel means to modulate polyQ aggregation and suggest that UL97 can serve as a novel tool to probe the cellular mechanisms that contribute to the formation of aggregates in polyglutamine disorders.
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PMID:Human cytomegalovirus UL97 kinase prevents the deposition of mutant protein aggregates in cellular models of Huntington's disease and ataxia. 2073 21


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