Human Molecular Genetics Advance Access originally published online on July 21, 2004
Human Molecular Genetics 2004 13(18):2019-2030; doi:10.1093/hmg/ddh208
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Human Molecular Genetics, Vol. 13, No. 18 © Oxford University Press 2004; all rights reserved
A Drosophila model of early onset torsion dystonia suggests impairment in TGF-ß signaling
Laboratory of Genetics, 445 Henry Mall, University of Wisconsin Madison, Madison, WI 53706, USA
Received May 3, 2004; Revised June 23, 2004; Accepted July 1, 2004
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 (
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 in larvae expressing E HtorA were observed at the EM level, some of which resemble those recently reported for mutants with defects in TGF-ß 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-ß signaling from synapses to endosomes or nuclei. Consistent with this possibility, neuronal overexpression of Drosophila or human Smad2, a downstream effector of the TGF-ß pathway, suppressed the behavioral and ultrastructural defects of E HtorA flies. These results raise the possibility that a defect in TGF-ß signaling might also underlie early onset torsion dystonia in humans.
* To whom correspondence should be addressed. Tel: +1 6082623896; Fax: +1 6082622976; Email: ganetzky{at}wisc.edu
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