No abstract

No 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.

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.

protein), which is a key member of the SNARE (soluble N-ethylmaleimidesensitive fusion protein attachment protein receptor) core complex that is essential for exocytosis. Both in vitro and in vivo experiments demonstrate that activation of PKC results in phosphorylation of SNAP-25 at Ser187. However, the importance of SNAP-25 phosphorylation at Ser187 in PKC-mediated enhancement of exocytosis has not been fully studied. Here, I investigated the importance of SNAP-25 phosphorylation at Ser187 upon activation of PKC by a phorbol ester to stimulate exocytosis in rat insulin-secreting INS-1 cells. With the transfection of botulinium toxin E (BoNT/E) to disable the endogenous SNAP-25, my results show that SNAP-25 phosphorylation at Ser187 is important for phorbol ester-enhanced exocytosis. However, my results also indicate that SNAP-25 phosphorylation at Ser187 is not the only mechanism involved in phorbol ester-enhanced exocytosis at high [Ca2+]i. This work helps clarify the molecular mechanisms by which phorbol ester and PKC enhance exocytosis. It also contributes to our understanding of the role of SNAP-25 in exocytosis.