A Drosophila model of early onset torsion dystonia suggests impairment in TGF-β signaling

• Published in: Human molecular genetics 2004-09, Vol.13 (18), p.2019-2030
• Main Authors: Koh, Young-Ho, Rehfeld, Kimberly, Ganetzky, Barry
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Disease Models, Animal; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drosophila; Drosophila - cytology; Drosophila - genetics; Dystonia Musculorum Deformans - etiology; Dystonia Musculorum Deformans - genetics; Dystonia Musculorum Deformans - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression; Genetics of eukaryotes. Biological and molecular evolution; Glutamic Acid - genetics; Humans; Medical sciences; Molecular and cellular biology; Molecular Chaperones - analysis; Molecular Chaperones - genetics; Molecular Chaperones - metabolism; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Neurons - immunology; Neurons - metabolism; Sequence Deletion; Signal Transduction - genetics; Smad2 Protein; Synapses - ultrastructure; Trans-Activators - genetics; Trans-Activators - metabolism; Transforming Growth Factor beta - physiology
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddh208

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 (ΔE HtorA), but not normal HtorA, elicits locomotor defects in Drosophila. As in mammalian systems, ΔE HtorA in flies forms protein accumulations that localize to synaptic membranes, nuclei and endosomes. Various morphological defects at the neuromuscular junction in larvae expressing ΔE HtorA were observed at the EM level, some of which resemble those recently reported for mutants with defects in TGF-β signaling. These results together with the distribution patterns and localizations of ΔE HtorA accumulations suggested that ΔE HtorA could interfere with some aspect of TGF-β signaling from synapses to endosomes or nuclei. Consistent with this possibility, neuronal overexpression of Drosophila or human Smad2, a downstream effector of the TGF-β pathway, suppressed the behavioral and ultrastructural defects of ΔE HtorA flies. These results raise the possibility that a defect in TGF-β signaling might also underlie early onset torsion dystonia in humans.