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Human Molecular Genetics, 2000, Vol. 9, No. 9 1403-1413
© 2000 Oxford University Press

Mutant torsinA, responsible for early-onset torsion dystonia, forms membrane inclusions in cultured neural cells

Jeffrey Hewett+, Charo Gonzalez-Agosti+,§, Damien Slater, Philipp Ziefer, Sang Li, Daniele Bergeron, David J. Jacoby, Laurie J. Ozelius, Vijaya Ramesh and Xandra O. Breakefield{ddagger}

Molecular Neurogenetics Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

Early-onset torsion dystonia is a hereditary movement disorder thought to be caused by decreased release of dopamine into the basal ganglia, without apparent neuronal degeneration. Recent cloning of the gene responsible for this disease, TOR1A (DYT1), identified the encoded protein, torsinA, as a member of the AAA+ superfamily of chaperone proteins and revealed highest levels of expression in dopaminergic neurons in human brain. Most cases of this disease are caused by a deletion of one glutamic acid residue in the C-terminal region of the protein. Antibodies generated against torsinA revealed expression of a predominant immunoreactive protein species similar to the predicted size of 37.8 kDa in neural, glial and fibroblastic lines by western blot analysis. This protein is N-glycosylated with high mannose content and not, apparently, phosphoryl­ated. Overexpression of torsinA in mouse neural CAD cells followed by immunocytochemistry, revealed a dramatically different pattern of distribution for wild-type and mutant forms of the protein. The wild-type protein was found throughout the cytoplasm and neurites with a high degree of co-localization with the endoplasmic reticulum (ER) marker, protein disulfide isomerase. In contrast, the mutant protein accumulated in multiple, large inclusions in the cytoplasm around the nucleus. These inclusions were composed of membrane whorls, apparently derived from the ER. If disrupted processing of the mutant protein leads to its accumulation in multilayer membranous structures in vivo, these may interfere with membrane trafficking in neurons.

+ These authors contributed equally to this work

§ Present address: Department of Psychiatry Research, University of Zürich, 8008 Zürich, Switzerland

Present address: Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA

{ddagger} To whom correspondence should be addressed at: Massachusetts General Hospital-East, Department of Molecular Neurogenetics, 13th Street, Building 149, 6th floor, Charlestown, MA 02129, USA. Tel: +1 617 726 5728; Fax: +1 617 724 1537; Email: breakefi@helix.mgh.harvard.edu


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