Title :
Torsin A and its torsion dystonia-associated mutant forms are lumenal
glycoproteins that exhibit distinct subcellular localizations
Abstract :
- Early-onset torsion dystonia is an autosomal dominant hyperkinetic movement disorder that has recently been linked to a 3-base pair deletion in the DYT1 gene
- The DYT1 gene encodes a 332-amino acid protein , torsin A , that bears low but significant homology to the Hsp100 / Clp family of ATPase chaperones
- The deletion in DYT1 associated with torsion dystonia results in the loss of one of a pair of glutamic acid residues residing near the C terminus of torsin A (DeltaE- torsin A )
- At present, little is known about the expression, subcellular distribution, and/or function of either the torsin A or DeltaE- torsin A protein
- When transfected into mammalian cells, both torsin A and DeltaE- torsin A were found to behave as lumenally oriented glycoproteins
- Immunofluorescence studies revealed that torsin A localized to a diffuse network of intracellular membranes displaying significant co-immunoreactivity for the endoplasmic reticulum resident protein BiP , whereas DeltaE- torsin A resided in large spheroid intracellular structures exclusive of BiP immunoreactivity
- These results initially suggested that DeltaE- torsin A might exist as insoluble aggregates
- However, both torsin A and DeltaE- torsin A were readily solubilized by nonionic detergents, were similarly accessible to proteases, and displayed equivalent migration patterns on sucrose gradients
- Collectively, these data support that both the wild type and torsion dystonia-associated forms of torsin A are properly folded, lumenal proteins of similar oligomeric states
- The potential relationship between the altered subcellular distribution of DeltaE- torsin A and the disease-inducing phenotype of the protein is discussed