Abstract
Dystonia represents the third most common movement disorder in humans with over 20 genetic loci identified. TOR1A (DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. Most cases of DYT1 dystonia are caused by a 3 bp (ΔGAG) deletion that results in the loss of a glutamic acid residue (ΔE302/303) in the carboxyl terminal region of torsinA. This torsinAΔE mutant protein has been speculated to act in a dominant-negative manner to decrease activity of wild type torsinA. Drosophila melanogaster has a single torsin-related gene, dtorsin. Null mutants of dtorsin exhibited locomotion defects in third instar larvae. Levels of dopamine and GTP cyclohydrolase (GTPCH) proteins were severely reduced in dtorsin-null brains. Further, the locomotion defect was rescued by the expression of human torsinA or feeding with dopamine.Here, we demonstrate that human torsinAΔE dominantly inhibited locomotion in larvae and adults when expressed in neurons using a pan-neuronal promoter Elav. Dopamine and tetrahydrobiopterin (BH4) levels were significantly reduced in larval brains and the expression level of GTPCH protein was severely impaired in adult and larval brains. When human torsinA and torsinAΔE were co-expressed in neurons in dtorsin-null larvae and adults, the locomotion rates and the expression levels of GTPCH protein were severely reduced. These results support the hypothesis that torsinAΔE inhibits wild type torsinA activity. Similarly, neuronal expression of a Drosophila DtorsinΔE equivalent mutation dominantly inhibited larval locomotion and GTPCH protein expression. These results indicate that both torsinAΔE and DtorsinΔE act in a dominant-negative manner. We also demonstrate that Dtorsin regulates GTPCH expression at the post-transcriptional level. This Drosophila model of DYT1 dystonia provides an important tool for studying the differences in the molecular function between the wild type and the mutant torsin proteins.
Highlights
Dystonia is the third most common movement disorder in humans, after essential tremor and Parkinson’s disease (Defazio, 2010)
Human torsinADE dominantly inhibits larval locomotion In the previous study, we analyzed the peristaltic frequency of third instar larvae to quantify the difference in locomotion between wild type and mutant
The wild type human torsinA cDNA expressed with the pan-neuronal driver elavGAL4 rescued dtorsinKO13 male larval mobility to a very significant level (56.363.7, n514, p,0.0001) (Fig. 1A, column 7) (Wakabayashi-Ito et al, 2011), compared to dtorsinKO13 male larvae with the elavGAL4 transgene (27.261.1, n539) (Fig. 1A, column 6)
Summary
Dystonia is the third most common movement disorder in humans, after essential tremor and Parkinson’s disease (Defazio, 2010). Dystonia comprises a group of movement disorders that are characterized by involuntary movements and abnormal postures It is a complex disease involving at least 20 genetic loci in humans (Tarsy and Simon, 2006; Breakefield et al, 2008; Bruggemann and Klein, 2010). TOR1A/DYT1, is responsible for most cases of early-onset dystonia and has been the most studied form of dystonia (Breakefield et al, 2001; Atai et al, 2012; Bragg et al, 2011) It is an autosomal dominant syndrome with onset between 5 to 28 years of age and low penetrance. The torsinADE (DE302/303) mutant protein has been speculated to act in a dominant-negative manner, so that the wild type function is reduced but not eliminated in the cells expressing both torsinA and torsinADE, this has never been clearly demonstrated (Breakefield et al, 2001; Breakefield et al, 2008)
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