
TorsinA is an AAA+ ATPase located within the lumen of the endoplasmic reticulum and nuclear envelope, with a mutant form causing early onset torsion dystonia (DYT1). Here we report a new function for torsinA in endoplasmic reticulum-associated degradation (ERAD). Retro-translocation and proteosomal degradation of a mutant cystic fibrosis transmembrane conductance regulator (CFTRΔF508) was inhibited by downregulation of torsinA or overexpression of mutant torsinA, and facilitated by increased torsinA. Retro-translocation of cholera toxin was also decreased by downregulation of torsinA. TorsinA associates with proteins implicated in ERAD, including Derlin-1, VIMP and p97. Further, torsinA reduces endoplasmic reticulum stress in nematodes overexpressing CFTRΔF508, and fibroblasts from DYT1 dystonia patients are more sensitive than controls to endoplasmic reticulum stress and less able to degrade mutant CFTR. Therefore, compromised ERAD function in the cells of DYT1 patients may increase sensitivity to endoplasmic reticulum stress with consequent alterations in neuronal function contributing to the disease state.
Cholera Toxin, Proteasome Endopeptidase Complex, Blotting, Western, Dystonia Musculorum Deformans, 610, Cystic Fibrosis Transmembrane Conductance Regulator, 612, Endoplasmic Reticulum, Article, cystic fibrosis, Mice, Chlorocebus aethiops, Animals, Humans, Immunoprecipitation, retro-translocation, Analysis of Variance, cholera toxin, Fibroblasts, Immunohistochemistry, secretory pathway, Mice, Inbred C57BL, COS Cells, protein degradation, proteosome, dystonia, movement disorder, Protein Processing, Post-Translational, Molecular Chaperones
Cholera Toxin, Proteasome Endopeptidase Complex, Blotting, Western, Dystonia Musculorum Deformans, 610, Cystic Fibrosis Transmembrane Conductance Regulator, 612, Endoplasmic Reticulum, Article, cystic fibrosis, Mice, Chlorocebus aethiops, Animals, Humans, Immunoprecipitation, retro-translocation, Analysis of Variance, cholera toxin, Fibroblasts, Immunohistochemistry, secretory pathway, Mice, Inbred C57BL, COS Cells, protein degradation, proteosome, dystonia, movement disorder, Protein Processing, Post-Translational, Molecular Chaperones
| selected citations These citations are derived from selected sources. This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically). | 103 | |
| popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network. | Top 10% | |
| influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically). | Top 10% | |
| impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network. | Top 10% |
