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A predictable worm: application of Caenorhabditis elegans for mechanistic investigation of movement disorders.

ABSTRACT: Ongoing investigations into causes and cures for human movement disorders are important toward the elucidation of diseases such as Parkinson's disease (PD) and dystonia. The use of animal model systems can provide links to susceptibility factors, as well as therapeutic interventions. In this regard, the nematode roundworm, Caenorhabditis elegans, is ideal for examining age-dependent neurodegenerative disease studies. It is genetically tractable, has a short lifespan, and a well-defined nervous system. Green fluorescent protein is readily visualized in C. elegans because it is a transparent organism, thus the nervous system and factors that alter the viability of neurons can be directly examined in vivo. Through expression of the human PD-associated protein (?-synuclein in the worm dopamine neurons), neurodegeneration is observed in an age-dependent manner. Furthermore, expression of the early-onset dystonia-related protein torsinA increases vulnerability to endoplasmic reticulum (ER) stress in C. elegans, because torsinA is located in the ER. Here we provide an overview of collaborative studies we have conducted that collectively demonstrate the usefulness of the nematode model to discern functional effectors of dopaminergic neurodegeneration and ER stress that translate to mammalian data in the fields of PD and dystonia. Taken together, the application of C. elegans toward the evaluation of genetic modifiers for movement disorders research has predictive value and serves to accelerate the path forward for therapeutic interventions.

SUBMITTER: Dexter PM

PROVIDER: S-EPMC3337026 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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A predictable worm: application of Caenorhabditis elegans for mechanistic investigation of movement disorders.

Dexter Paige M PM Caldwell Kim A KA Caldwell Guy A GA

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20120401 2

Ongoing investigations into causes and cures for human movement disorders are important toward the elucidation of diseases such as Parkinson's disease (PD) and dystonia. The use of animal model systems can provide links to susceptibility factors, as well as therapeutic interventions. In this regard, the nematode roundworm, Caenorhabditis elegans, is ideal for examining age-dependent neurodegenerative disease studies. It is genetically tractable, has a short lifespan, and a well-defined nervous s ...[more]

PMID: 22403010

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Project description:Soil bacteria can be prolific producers of secondary metabolites and other biologically active compounds of economic and clinical importance. These natural products are often synthesized by large multi-enzyme complexes such as polyketide synthases (PKSs) or non-ribosomal peptide synthases (NRPSs). The plant-associated Gram-negative bacterium, Serratia plymuthica A153, produces several secondary metabolites and is capable of killing the nematode worm Caenorhabditis elegans; a commonly used model for the study of bacterial virulence. In this study, we show that disruption of the hybrid PKS/NRPS zeamine (zmn) gene cluster results in the attenuation of "fast-killing" of C. elegans, indicating that zeamine has nematicidal activity. C. elegans also exhibits age-dependent susceptibility to zeamine, with younger worms being most sensitive to the bioactive molecule. The zmn gene cluster is widely distributed within Serratia and phytopathogenic Dickeya species and investigation of strains harboring the zmn gene cluster showed that several of them are highly virulent in C. elegans. Zeamine was described previously as a phytotoxin and broad-spectrum antibacterial compound. In addition to its nematicidal properties, we show here that zeamine can also kill Saccharomyces cerevisiae and Schizosaccharomyces pombe. The expression of the zmn gene cluster and regulation of zeamine production were also investigated. Transcription of the cluster was growth phase-dependent, and was modulated by the post-transcriptional RNA chaperone, Hfq. The results of this study show that zeamine is a highly toxic molecule with little, or no, apparent host specificity in very diverse biological systems. In its current form, zeamine(s) may be useful as a lead compound suitable for chemical modification and structure-activity assays. However, because of widespread non-selective toxicity in multiple bioassays, unmodified zeamine(s) is unlikely to be suitable as a therapeutic antibiotic.

Dataset Information

A predictable worm: application of Caenorhabditis elegans for mechanistic investigation of movement disorders.

Publications

A predictable worm: application of Caenorhabditis elegans for mechanistic investigation of movement disorders.

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