Human Molecular Genetics Advance Access published online on July 21, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh208
© 2004 by Oxford University Press
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1 Laboratory of Genetics, 445 Henry Mall, University of Wisconsin Madison, Madison, WI 53706, U.S.A.
* To whom correspondence should be addressed. E-mail: ganetzky{at}wisc.edu.
To investigate the cellular and molecular etiology of early-onset torsion dystonia, we have established a Drosophila model of this disorder. Expression of mutant human torsinA deleted for a single glutamic acid residue (
Article
A Drosophila model of early-onset torsion dystonia suggests impairment in TGF-
signaling
Abstract 
E HtorA), but not normal HtorA, elicits locomotor defects in Drosophila. As in mammalian systems, E HtorA in flies forms protein accumulations that localize to synaptic membranes, nuclei, and endosomes. Various morphological defects at the neuromuscular junction (NMJ) in larvae expressing E HtorA were observed at the EM level, some of which resemble those recently reported for mutants with defects in TGF-
signaling. These results together with the distribution patterns and localizations of E HtorA accumulations suggested that E HtorA could interfere with some aspect of TGF- signaling from synapses to endosomes or nuclei. Consistent with this possibility, neuronal overexpression of Drosophila or human Smad2, a downstream effector of the TGF- pathway, suppressed the behavioral and ultrastructural defects of E HtorA flies. These results raise the possibility that a defect in TGF- signaling might also underlie early-onset torsion dystonia in humans.
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