| pubmed-article:18940237 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:18940237 | lifeskim:mentions | umls-concept:C0026882 | lld:lifeskim |
| pubmed-article:18940237 | lifeskim:mentions | umls-concept:C1851945 | lld:lifeskim |
| pubmed-article:18940237 | lifeskim:mentions | umls-concept:C1540039 | lld:lifeskim |
| pubmed-article:18940237 | lifeskim:mentions | umls-concept:C0699900 | lld:lifeskim |
| pubmed-article:18940237 | lifeskim:mentions | umls-concept:C0243125 | lld:lifeskim |
| pubmed-article:18940237 | lifeskim:mentions | umls-concept:C0686907 | lld:lifeskim |
| pubmed-article:18940237 | pubmed:issue | 3 | lld:pubmed |
| pubmed-article:18940237 | pubmed:dateCreated | 2008-11-25 | lld:pubmed |
| pubmed-article:18940237 | pubmed:abstractText | DYT1 is the most common inherited dystonia, a neurological syndrome that causes disabling involuntary muscle contractions. This autosomal dominant disease is caused by a glutamic acid deletion near the carboxy-terminus in the protein torsinA. Cell- and animal-based studies have shown how the DYT1 mutation causes mutant torsinA to redistribute from the endoplasmic reticulum to the nuclear envelope, acting through a dominant negative effect over the wild type protein. As a result, the wild type:mutant torsinA expression ratio would be important for disease pathogenesis, and events that influence it, such as a differential degradation process for each protein, might modulate DYT1 pathobiology. The DYT1 mutation also triggers the formation of abnormal intermolecular disulfide bonds in torsinA, although the significance of this finding is unclear. How the protein quality control machinery handles torsinA, and whether this process is affected by its abnormal oligomerization remain unknown. Here, we first explored how the disease-linked mutation influences the catabolic process of human torsinA, demonstrating that the differences in subcellular localization between both forms of torsinA lead to divergences in their degradation pathways and, whereas torsinA is normally recycled through autophagy, the proteasome is also required for the efficient clearance of the mutated form. Subsequently, we determined that the abnormal disulfide bond-dependent oligomerization of mutant torsinA is not a result of its redistribution to the nuclear envelope, but a direct consequence of the mutation. Finally, we established that the presence of disulfide links in mutant torsinA oligomers interfere with their degradation by the proteasome, thus relying on autophagy as the main pathway for clearance. In conclusion, the abnormal subcellular localization and oligomerization of DYT1-linked torsinA influences its catabolic process, opening the door to the modulation of the wild type:mutant torsinA ratio through pharmacological manipulation of protein degradation pathways. | lld:pubmed |
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| pubmed-article:18940237 | pubmed:language | eng | lld:pubmed |
| pubmed-article:18940237 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:18940237 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:18940237 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:18940237 | pubmed:month | Dec | lld:pubmed |
| pubmed-article:18940237 | pubmed:issn | 0306-4522 | lld:pubmed |
| pubmed-article:18940237 | pubmed:author | pubmed-author:GordonK LKL | lld:pubmed |
| pubmed-article:18940237 | pubmed:author | pubmed-author:Gonzalez-Aleg... | lld:pubmed |
| pubmed-article:18940237 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:18940237 | pubmed:day | 2 | lld:pubmed |
| pubmed-article:18940237 | pubmed:volume | 157 | lld:pubmed |
| pubmed-article:18940237 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:18940237 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:18940237 | pubmed:pagination | 588-95 | lld:pubmed |
| pubmed-article:18940237 | pubmed:dateRevised | 2010-9-21 | lld:pubmed |
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| pubmed-article:18940237 | pubmed:meshHeading | pubmed-meshheading:18940237... | lld:pubmed |
| pubmed-article:18940237 | pubmed:year | 2008 | lld:pubmed |
| pubmed-article:18940237 | pubmed:articleTitle | Consequences of the DYT1 mutation on torsinA oligomerization and degradation. | lld:pubmed |
| pubmed-article:18940237 | pubmed:affiliation | Interdisciplinary Graduate Program in Neuroscience, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA. | lld:pubmed |
| pubmed-article:18940237 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:18940237 | pubmed:publicationType | Research Support, N.I.H., Extramural | lld:pubmed |
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