Suppression of polyglutamine-induced protein aggregation in Caenorhabditis elegans by torsin proteins

Torsion dystonia is an autosomal dominant movement disorder characterized by involuntary, repetitive muscle contractions and twisted postures. The most severe early-onset form of dystonia has been linked to mutations in the human DYT1 (TOR1A) gene encoding a protein termed torsinA. While causative g...

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Bibliographic Details
Published in:	Human molecular genetics Vol. 12; no. 3; pp. 307 - 319
Main Authors:	Caldwell, Guy A., Cao, Songsong, Sexton, Elaina G., Gelwix, Christopher C., Bevel, John Paul, Caldwell, Kim A.
Format:	Journal Article
Language:	English
Published:	Oxford Oxford University Press 01-02-2003 Oxford Publishing Limited (England)
Subjects:	Aging Amino Acid Sequence Animals Biological and medical sciences Caenorhabditis elegans - metabolism Caenorhabditis elegans Proteins - biosynthesis Caenorhabditis elegans Proteins - genetics Caenorhabditis elegans Proteins - metabolism Disease Models, Animal Diseases of striated muscles. Neuromuscular diseases Dystonia - genetics Dystonia - metabolism Medical sciences Molecular Chaperones - metabolism Molecular Sequence Data Mutation Neurology Peptides - metabolism Phosphotransferases (Alcohol Group Acceptor) - biosynthesis Phosphotransferases (Alcohol Group Acceptor) - genetics Phosphotransferases (Alcohol Group Acceptor) - metabolism Proteins - metabolism Sequence Alignment Animal model Nervous system diseases Functional analysis Polyaminoacid Protein Involuntary movement Aggregation Caenorhabditis elegans Striated muscle disease Helmintha Nemathelminthia Dystonia Invertebrata Neurological disorder Nematoda Extrapyramidal syndrome Glutamine
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Summary:	Torsion dystonia is an autosomal dominant movement disorder characterized by involuntary, repetitive muscle contractions and twisted postures. The most severe early-onset form of dystonia has been linked to mutations in the human DYT1 (TOR1A) gene encoding a protein termed torsinA. While causative genetic alterations have been identified, the function of torsin proteins and the molecular mechanism underlying dystonia remain unknown. Phylogenetic analysis of the torsin protein family indicates these proteins share distant sequence similarity with the large and diverse family of AAA+ proteins. We have established the nematode, Caenorhabditis elegans, as a model system for examining torsin activity. Using an in vivo assay for polyglutamine repeat-induced protein aggregation in living animals, we have determined that ectopic overexpression of both human and C. elegans torsin proteins results in a dramatic reduction of polyglutamine-dependent protein aggregation in a manner similar to that previously reported for molecular chaperones. The suppressive effects of torsin overexpression persisted as animals aged, whereas a mutant nematode torsin protein was incapable of ameliorating aggregate formation. Antibody staining of transgenic animals indicated that both the C. elegans torsin-related protein TOR-2 and ubiquitin were localized to sites of protein aggregation. These data represent the first functional evidence of a role for torsins in effectively managing protein folding and suggest that possible breakdown in a neuroprotective mechanism that is, in part, mediated by torsins may be responsible for the neuronal dysfunction associated with dystonia.
Bibliography:	local:ddg027 istex:F71855803A166B953546DD373513A708DD000E0C ark:/67375/HXZ-K7HZLZVN-J ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0964-6906 1460-2083 1460-2083
DOI:	10.1093/hmg/ddg027