In vivo dissection of neuroprotection using a novel c. elegans model of neurodegeneration

The discovery of neuroprotective genes and gene variants will open new therapeutic avenues for neurodegenerative diseases. Forward genetics in model organisms is an approach that dissects gene function. We will use high-throughput forward genetic approaches on the genetically tractable nematode C. elegans to discover neuroprotective genes. We have previously established a C. elegans model of neurodegeneration in which a mutation in a transient receptor potential (TRP) channel results in progressive loss of dopaminergic neurons.

Building on this model, we have engineered a novel strain suitable for automated phenotyping and mutagenesis-based screening. We performed a pilot screen and isolated 18 different mutants that are resistant to TRP-channel induced neuronal loss. We aim to identify the causal mutations for neuroprotection in the 18 isolated mutants, test whether the mutations that protect dopaminergic neurons in our model are also protective in other models of neurodegenerative disease, such as Parkinson’s, tauopathy and excitotoxicity C. elegans models, and perform preliminary characterisation of selected neuroprotective genes.

This research will provide insights into human neurodegenerative disease and set the groundwork for future in-depth mechanistic investigations of neuroprotection and collaborative translational research projects.