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.
Highlights
The complexity of the human nervous system represents a daunting challenge for researchers to attain a mechanistic understanding of the underlying cellular and molecular features responsible for disease onset and progression
Mammalian models are invaluable tools for examining the DYT gene products, especially considering the wide range of clinical features associated with dystonia, such as muscle contraction, tremors, and/or myoclonus [3,4,5], that may illustrate under-explored aspects of neuronal misregulation. These models may not recapitulate all pathological impairments of dystonia and are expensive. Despite their lack of evolutionary complexity, invertebrate model organisms, such as Drosophila melanogaster and Caenorhabditis elegans have been utilized in first pass screens for examining cellular mechanisms, as well as identifying genes and drugs that might be therapeutically relevant to molecular processes underlying dystonia
We have outlined distinct facets of C. elegans and Drosophila models that have provided significant insights into how specific disease-related proteins contribute to the dysfunction associated with dystonia
Summary
The complexity of the human nervous system represents a daunting challenge for researchers to attain a mechanistic understanding of the underlying cellular and molecular features responsible for disease onset and progression. These gene products are torsinA (DYT1), TAF1 (DYT3), GTP-cyclohydrolase 1 (DYT5a), tyrosine hydroxylase (DYT5b), THAP1 (DYT6), myofibrillogenesis regulator 1 (DYT8), ε-sarcoglycan (DYT11), Na+/K+ ATPase α3 subunit (DYT12), PRKRA (DYT16), and SLC2A1 (DYT18) [2] These findings provide the opportunity to develop animal models for in vivo evaluation of the encoded proteins, as well as identification of genetic and/or physical interactions. These models may not recapitulate all pathological impairments of dystonia and are expensive In this regard, despite their lack of evolutionary complexity, invertebrate model organisms, such as Drosophila melanogaster and Caenorhabditis elegans have been utilized in first pass screens for examining cellular mechanisms, as well as identifying genes and drugs that might be therapeutically relevant to molecular processes underlying dystonia. They offer economical, yet strategic experimental paradigms that provide rapid analyses of pathological cellular mechanisms associated with dystonia
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