C. elegans models of neuromuscular diseases expedite translational research

Abstract

The nematode Caenorhabditis elegans is a genetic model organism and the only animal with a complete nervous system wiring diagram. With only 302 neurons and 95 striated muscle cells, a rich array of mutants with defective locomotion and the facility for individual targeted gene knockdown by RNA interference, it lends itself to the exploration of gene function at nerve muscle junctions. With approximately 60% of human disease genes having a C. elegans homologue, there is growing interest in the deployment of lowcost, high-throughput, drug screens of nematode transgenic and mutant strains mimicking aspects of the pathology of devastating human neuromuscular disorders. Here we explore the contributions already made by C. elegans to our understanding of muscular dystrophies (Duchenne and Becker), spinal muscular atrophy, amyotrophic lateral sclerosis, Friedreich’s ataxia, inclusion body myositis and the prospects for contributions to other neuromuscular disorders. A bottleneck to low-cost, in vivo, large-scale chemical library screening for new candidate therapies has been rapid, automated, behavioural phenotyping. Recent progress in quantifying simple swimming (thrashing) movements is making such screening possible and is expediting the translation of drug candidates towards the clinic.

Physical exertion exacerbates decline in the musculature of an animal model of Duchenne muscular dystrophy

“…For decades, the nematode Caenorhabditis elegans has been fruitfully used to model human disorders (22). C. elegans worms that genetically model DMD through loss-of-function mutations in dystrophin homolog (dys-1) are hyperactive and hypercontracted (23).…”

Invertebrate models of spinal muscular atrophy: Insights into mechanisms and potential therapeutics

“…Like the fruit fly, there is a surprisingly high level of genetic conservation between humans and the worm and many biochemical pathways are well conserved 60–62, which is essential for the dissection of pathological mechanisms of disease and the identification of compounds with the potential to treat them. Accordingly, C. elegans has been used to model numerous nervous system and neuromuscular disorders, and is a common tool for large‐scale screening of genetic knockdown and chemical compound libraries 63, 64.…”

“…C. elegans serves as unrivalled first‐pass filter for screening large chemical compound libraries for drugs with therapeutic potential 64. Similar to RNAi library screening, large quantities of drugs can be tested in C. elegans prior to validation in vertebrate models.…”

Methodological advances in imaging intravital axonal transport

“…The sophisticated genetic toolboxes of Caenorhabditis elegans and Drosophila melanogaster allow the specific targeting of fluorescent proteins to vesicles and organelles such as mitochondria. When coupled with the ever-expanding repertoire of neurological disease-relevant worm and fly models 31 – 34 , these reporter lines provide a powerful system for analysing the axonal transport of assorted cargoes in both ageing and disease 35 – 40 . Transport studies in Drosophila have largely been performed in filleted larval preparations rather than adult flies, limiting the time period over which analyses can be performed and the developmental stage of the neurons under investigation.…”