Title:Invertebrate Models of Dystonia
Volume: 11
Issue: 1
Author(s): Kim A. Caldwell, Yilong Shu, Nathan B. Roberts, Guy A. Caldwell and Janis M. O’Donnell
Affiliation:
Keywords:
Drosophila, C. elegans, torsinA, GTP-cyclohydrolase 1, Na+/K+ ATPase a3 subunit
Abstract: The neurological movement disorder dystonia is an umbrella term for a heterogeneous group of related
conditions where at least 20 monogenic forms have been identified. Despite the substantial advances resulting from the
identification of these loci, the function of many DYT gene products remains unclear. Comparative genomics using
simple animal models to examine the evolutionarily conserved functional relationships with monogenic dystonias
represents a rapid route toward a comprehensive understanding of these movement disorders. Current studies using the
invertebrate animal models Caenorhabditis elegans and Drosophila melanogaster are uncovering cellular functions and
mechanisms associated with mutant forms of the well-conserved gene products corresponding to DYT1, DYT5a, DYT5b,
and DYT12 dystonias. Here we review recent findings from the invertebrate literature pertaining to molecular
mechanisms of these gene products, torsinA, GTP cyclohydrolase I, tyrosine hydroxylase, and the alpha subunit of Na+/K
ATPase, respectively. In each study, the application of powerful genetic tools developed over decades of intensive work
with both of these invertebrate systems has led to mechanistic insights into these human disorders. These models are
particularly amenable to large-scale genetic screens for modifiers or additional alleles, which are bolstering our
understanding of the molecular functions associated with these gene products. Moreover, the use of invertebrate models
for the evaluation of DYT genetic loci and their genetic interaction networks has predictive value and can provide a path
forward for therapeutic intervention.
