Using Caenorhabditis elegans to fight human neurodegenerative diseases

Debilitating neurodegenerative disorders (NDs) including Alzheimer’s disease, Parkinson’s disease, and polyglutamine diseases are a major public health challenge in increasingly aging societies. Currently approved therapeutics are successful in slowing the progression of NDs but not in reversing or preventing the symptoms of NDs. The simplicity and amenability of the nematode Caenorhabditis elegans (C. elegans) to high-throughput genomic, proteomic and drug screening approaches make this organism an attractive choice for identifying new therapeutic compounds for these disorders and for understanding their mechanism of action. Indeed, a diverse set of informative C. elegans ND models have been developed manifesting abnormal behavioural or pathological phenotypes that partially recapitulate the salient cellular, molecular and pathological aspects of several distinct human NDs processes. Recent studies have identified dnajc5 encoding cysteine-string protein α (CSPα) as the disease-causing gene of a rare autosomal dominant human ND known as adult-onset neuronal ceroid lipofuscinosis (ANCL). The null animal models of CSP are characterised by impaired neurotransmission, pre-synaptic neurodegeneration and premature mortality. Simple model organisms may therefore shed light on potential therapeutic approaches for ANCL and other NDs.

In this study, we are integrating multiple well-defined C. elegans ND models to uncover potential therapeutic interventions that target shared pathogenic pathways. We tested parameters such as locomotion and lifespan which act as a measure of neurological and neuromuscular function, and viability upon drug treatment in C. elegans.

Overall, our data provide good evidence that anti-epileptic ethosuximide is efficacious in several worm ND models. Further investigation of its precise mode of action and validation in vertebrate systems is required to gauge the effectiveness of this compound as early leads for drug discovery. These findings should encourage further screening and characterisation of other neuroprotective compounds, and ultimately may assist in accelerating the clinical evaluation and development of drugs to combat protein conformational disorders in general.