? Dystonia is estimated to be six times more prevalent than Huntington's Disease, ALS, or Muscular Dystrophy. However, as few as 5% of the over 350,000 persons in North America estimated to be affected have been correctly diagnosed and are under treatment (NIH Budget Office). The most severe early-onset form of this disorder has been linked to a mutation in a human gene named TOR1A that encodes torsinA, a protein that is also localized to inclusions in the brains of Parkinson's patients termed Lewy bodies. While a causative genetic mutation has been identified, the cellular mechanisms of pathogenesis underlying dystonia remain unknown. We are applying the advantages of the model organism, Caenorhabditis elegans, towards a detailed analysis of two specific torsin-related gene products in this nematode. The chromosomal positioning of these genes suggests that they may represent a functionally co-expressed unit and preliminary studies from our laboratory indicate they act neuronally. Phylogenetic analysis of the torsin family indicates these proteins share distant sequence similarity with the functionally diverse AAA+ family of proteins. We have determined that ectopic overexpression of a C. elegans torsin homolog results in a reduction of polyglutamine repeat-induced protein aggregation in a manner similar to that previously reported for molecular chaperones. The suppressive effects of torsin overexpression quantitatively persisted as animals aged. Antibody staining of transgenic animals using antisera specific to TOR-2 indicated this protein was highly localized to sites of protein aggregation. We propose to extend these preliminary studies through a combination of reverse genetic approaches designed to investigate the cellular role of torsin proteins in the nematode.
The specific aims of the proposed project include: 1) to determine what phenotypes are associated with C. elegans torsin homologues; 2) to define sites of C. elegans torsin protein function; and 3) to determine potential effectors of torsin activity. These studies will further our understanding of the molecular mechanisms responsible for early-onset torsion dystonia. Moreover, the aberrant protein deposition associated with diverse neurodegenerative disorders like Parkinson's Disease and those caused by polyglutamine expansion such as Huntington's Disease warrants further investigation of any putative neuroprotective effects of torsins. ? ?
| Cao, Songsong; Hewett, Jeffrey W; Yokoi, Fumiaki et al. (2010) Chemical enhancement of torsinA function in cell and animal models of torsion dystonia. Dis Model Mech 3:386-96 |
| Chen, Pan; Burdette, Alexander J; Porter, J Christopher et al. (2010) The early-onset torsion dystonia-associated protein, torsinA, is a homeostatic regulator of endoplasmic reticulum stress response. Hum Mol Genet 19:3502-15 |
