Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A single GAG deletion in the DYT1 gene causes primary early-onset, generalized torsion dystonia. The DYT1 protein product, torsinA, belongs to the AAA+ family of proteins. When overexpressed, wild-type torsinA localizes mainly to the endoplasmic reticulum, whereas the mutant forms inclusions of unclear biogenetic origin. In this study, overexpressed wild-type torsinA in human neuroblastoma (SH-SY5Y) cell lines was distributed throughout the cell body and colocalized with a marker for the endoplasmic reticulum, confirming it is an endoplasmic reticulum protein. However, mutant torsinA showed perinuclear staining and formed distinct globular inclusions, which did not colocalize with endoplasmic reticulum markers. Immunoelectron microscopy of the mutant torsinA inclusions revealed membrane whorls staining for torsinA, as well as labeling of lamellae, isolated bilayers, and perinuclear membranes. This finding shows that mutant torsinA redistributes to specific membranous structures, which may represent different stages of maturation of the intracellular inclusions. The mutant torsinA-containing bodies were immunoreactive for vesicular monoamine transporter 2 (VMAT2). VMAT2 expression is important for the exocytosis of bioactive monoamines in neurons. Abnormal processing, transport, or entrapment of VMAT2 within the mutant torsinA membranous inclusions, therefore, may affect cellular dopamine release, providing a potential pathogenic mechanism for the DYT1-dependent dystonia.
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PMID:Mutant torsinA, which causes early-onset primary torsion dystonia, is redistributed to membranous structures enriched in vesicular monoamine transporter in cultured human SH-SY5Y cells. 1559 17

Early onset torsion dystonia is a movement disorder inherited as an autosomal dominant syndrome with reduced penetrance. Symptoms appear to result from altered neuronal circuitry within the brain with no evidence of neuronal loss. Most cases are caused by loss of a glutamic acid residue in the AAA+ chaperone protein, torsinA, encoded in the DYT1 gene. In this study, torsinA was found to move in conjunction with vimentin in three cell culture paradigms-recovery from microtubule depolymerization, expression of a dominant-negative form of kinesin light chain and respreading after trypsinization. Co-immune precipitation studies revealed association between vimentin and torsinA in a complex including other cytoskeletal elements, actin and tubulin, as well as two proteins previously shown to interact with torsinA-the motor protein, kinesin light chain 1, and the nuclear envelope protein, LAP1. Morphologic and functional differences related to vimentin were noted in primary fibroblasts from patients carrying this DYT1 mutation as compared with controls, including an increased perinuclear concentration of vimentin and a delayed rate of adhesion to the substratum. Overexpression of mutant torsinA inhibited neurite extension in human neuroblastoma cells, with torsinA and vimentin immunoreactivity enriched in the perinuclear region and in cytoplasmic inclusions. Collectively, these studies suggest that mutant torsinA interferes with cytoskeletal events involving vimentin, possibly by restricting movement of these particles/filaments, and hence may affect development of neuronal pathways in the brain.
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PMID:Dystonia-causing mutant torsinA inhibits cell adhesion and neurite extension through interference with cytoskeletal dynamics. 1636 Nov 7

The TOR1A (also named DYT1) gene encodes a protein, TorsinA, a member of the AAA+ superfamily of ATPases. The AAA+ proteins have diverse functions such as organelle biogenesis, proteosome function, chaperone function, membrane trafficking and microtubule regulation. However, the molecular function of TorsinA is still largely unknown. Mutations in the TOR1A gene, primarily a 3-bp (GAG) deletion are associated with early-onset autosomal dominant torsion dystonia. Animal models may help to provide information about the underlying cellular and molecular mechanism of early-onset generalized dystonia. The close anatomical, physiological, genetic and biochemical resemblance between man and pig suggest that this animal may constitute an excellent model for this disease. This work reports the cloning and analysis of the porcine (Sus scrofa) homologue of TOR1A. Two porcine TOR1A cDNAs were amplified by reverse transcriptase polymerase chain reaction (RT-PCR), using oligonucleotide primers derived from in silico sequences. The porcine TOR1A cDNAs both encode a protein of 333 amino acids which shows a very high similarity to human (92%) TorsinA. Protein structure comparison of human and porcine TorsinA sequences revealed that there were few differences in the amino acid sequences between the two species and these are not likely to alter TorsinA structure and function. Quantitative real-time RT-PCR detection exhibited TOR1A mRNA expression in all analyzed porcine tissues, although at different levels. The TOR1A gene was demonstrated to be localized on porcine chromosome 1. Single nucleotide polymorphism (SNP) analysis revealed several SNPs in the porcine TOR1A gene, both in the coding region and also in the 3' UTR region. Overexpression of mutant (DeltaE303-304) porcine TorsinA in neuroblastoma cells leads to a more perinuclear localization compared with a cytoplasmatic localization for wildtype TorsinA. Furthermore, inclusion-like structures were observed. In conclusion, the results obtained for porcine TOR1A suggest that the pig could be an ideal model for early-onset generalized dystonia.
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PMID:Characterization of the porcine TOR1A gene: The first step towards generation of a pig model for dystonia. 1902 53

A specific mutation (DeltaE302/303) in the torsinA gene underlies most cases of dominantly inherited early-onset torsion dystonia. This mutation causes the protein to aggregate and form intracellular inclusion bodies in cultured cells and animal models. Co-expression of the wildtype and mutant proteins resulted in the redistribution of the wildtype protein from the endoplasmic reticulum to inclusion bodies in cultured HEK293 cells, and this was associated with increased interaction between the two proteins. Expression of DeltaE302/303 but not wildtype torsinA in primary postnatal midbrain neurons resulted in the formation of intracellular inclusion bodies, predominantly in dopaminergic neurons. Tyrosine hydroxylase was sequestered in these inclusions and this process was mediated by increased protein-protein interaction between mutant torsinA and tyrosine hydroxylase. Analysis in an inducible neuroblastoma cell culture model demonstrated altered tyrosine hydroxylase activity in the presence of the mutant but not wildtype torsinA protein. Our results suggest that the interaction of tyrosine hydroxylase and mutant torsinA may contribute to the phenotype and reported dopaminergic dysfunction in torsinA-mediated dystonia.
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PMID:Mutant torsinA interacts with tyrosine hydroxylase in cultured cells. 1976 14