Abstract
Caenorhabditis elegans has emerged as a powerful model organism for drug screening due to its cellular simplicity, genetic amenability and homology to humans combined with its small size and low cost. Currently, high-throughput drug screening assays are mostly based on image-based phenotyping with the focus on morphological-descriptive traits not exploiting key locomotory parameters of this multicellular model with muscles such as its thrashing force, a critical biophysical parameter when screening drugs for muscle-related diseases. In this study, we demonstrated the use of a micropillar-based force assay chip in combination with a fluorescence assay to evaluate the efficacy of various drugs currently used in treatment of neurodegenerative and neuromuscular diseases. Using this two-dimensional approach, we showed that the force assay was generally more sensitive in measuring efficacy of drug treatment in Duchenne Muscular Dystrophy and Parkinson’s Disease mutant worms as well as partly in Amyotrophic Lateral Sclerosis model. These results underline the potential of our force assay chip in screening of potential drug candidates for the treatment of neurodegenerative and neuromuscular diseases when combined with a fluorescence assay in a two-dimensional analysis approach.
Highlights
Neuromuscular diseases consist of a diverse group of medical conditions that mainly affect the one or more parts of the neuromuscular unit such as skeletal muscle, motor neurons, peripheral nerves and neuromuscular synapses [1]
Using this two-dimensional approach, we showed that the force assay was generally more sensitive in measuring efficacy of drug treatment in Duchenne Muscular Dystrophy and Parkinson’s Disease mutant worms as well as partly in Amyotrophic Lateral Sclerosis model
We evaluated the thrashing force exerted by Duchenne muscular dystrophies (DMD) (LS587), Amyotrophic Lateral Sclerosis (ALS) (AM725) and Parkinson’s Disease (NL5901) mutant worms compared to wild-type N2
Summary
Neuromuscular diseases consist of a diverse group of medical conditions that mainly affect the one or more parts of the neuromuscular unit such as skeletal muscle, motor neurons, peripheral nerves and neuromuscular synapses [1]. These diseases which can be hereditary or acquired, affect as many as 1 in 3,000 people [2] and can be attributed to neurodegenerative diseases like Parkinson’s disease (PD) [3] and Duchenne muscular dystrophies (DMD) [4]. In modeling of neuromuscular diseases, it is important that neuronal cellular functions and muscle structure are well conserved if drugs are to be translated to humans.
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