Ongoing investigations into causes and cures for human movement disorders are important toward the elucidation of diseases, such as Parkinson’s disease (PD). 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 age-dependent neurodegenerative disease studies. It is genetically tractable, has a short life span, and a well-defined nervous system. Fluorescent markers, like GFP, are readily visualized in C. elegans as 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 disease protein, alpha-synuclein, in the worm dopamine neurons, neurodegeneration is observed in an age-dependent manner. Furthermore, application of a dopamine neurotoxin, 6-hydroxy-dopamine, provides another independent model of PD. Described herein are techniques for C. elegans transformation to evaluate candidate neuroprotective gene targets, integration of the extrachromosomal arrays, genetic crosses, and methods for dopamine neuron analysis that are applicable to both types of neurotoxicity. These techniques can be exploited to assess both chemical and genetic modifiers of toxicity, providing additional avenues to advance PD-related discoveries.
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We would like to thank all members of the Caldwell laboratory, especially Songsong Cao, Shusei Hamamichi, and Laura Berkowitz, for their contributions to the development of the methods described herein. Research on movement disorders in the Caldwell lab is supported by grants from the Howard Hughes Medical Institute (GAC), National Science Foundation (KAC), and QRxPharma, Ltd. (GAC and KAC).
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