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.
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