Objective: Development of a fast and unbiased screening method to identify C. elegans mutants with movement disabilities and drugs to improve impaired locomotion.

Background: Identifying mechanisms underlying all types of diseases is extremely important for the development of new therapies, but studying this in humans is often unfeasible and model organisms are essential. Our lab uses the nematode C. elegans to model motor-neuron diseases and other neurological disorders, such as Autism spectrum disorders (ASD). C. elegans is well-suited for neuroscience research thanks to its detailed neuronal lineage and synapse interconnectivity that resembles well those of the vertebrate nervous system. A genetic disease model ideally shows a distinct phenotype, such as impaired locomotion. Here we describe an approach to identify C. elegans models for ASD, and drugs that potentially modulate certain phenotypes associated with a specific gene mutation.

Methods: We examined 27 genes strongly linked to ASD that have orthologs in C. elegans and viable loss-of-function (LOF) mutants. We screened these mutants for motor-deficiency phenotypes that can be exploited to identify underlying mechanisms and for drug discovery purposes. The screening was performed using a worm tracking apparatus (Wmicrotracker, Phylum Tech). This machine tracks the activity of C. elegans both automatically and simultaneously (since it uses 96-well-plate formats), making high-throughput screenings possible. Worms were put in buffer and their swimming movements were tracked. Motor-deficient mutants that had been identified in this screen were then used in a comprehensive drug screen, which comprises ∼3800 FDA-approved compounds. These were analyzed for their ability to suppress motility defects caused by ASD mutations.

Results: From the 27 genes tested, 14 showed a motor-deficient phenotype. Of these, we picked 6 strains to perform the drug screen. Promising drugs have been identified and are under further examination.

Conclusions: New approaches to gain insights in the extremly complex mechanisms of ASD and other neurological disorders are of great significance. Establishing C. elegans models for ASD and screening of a well-characterized compound library might be a promising first step to understand the mechanisms underlying neuronal dysfunction. Positively tested substances could also be promising candidates for clinical studies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-rapid-chemical-genetic-screen-utilising-impaired-movement-phenotypes-in-caenorhabditis-elegans/