Motor Neurone Diseases (MNDs), such as amyotrophic lateral sclerosis (ALS), are neurodegenerative disorders specifically affecting the neurons that control muscle (motor neurons). Degeneration of the axonal domain of motor neurons is hypothesised to be causative of many MNDs. Only a handful of genes have been linked to MND pathology or to axonal degeneration, and therefore the genetic pathways responsible for these processes are largely uncharacterised.
We are focusing on the 19 GABAergic ventral nerve cord motor neurons of C. elegans, the DD and VD sub-classes. These neurons innervate the body wall muscle and control the locomotion of C. elegans, making them functional equivalents of the motor neurons targeted in MNDs. We aim to use these cells as a model to discover and characterise novel genes and mutations responsible for the axonal degeneration of motor neurons.
Using transgenic strains in which the DD and VD motor neurons are highlighted with GFP, we have conducted forward genetic screens and observed morphological changes indicative of axonal degeneration in these neurons. This observation suggests that genetic factors governing the axonal degeneration of motor neurons exist and are susceptible to mutagenesis. To complement the forward genetics, we are using a candidate-gene approach focusing on genes orthologous to human MND genes, such as
sod-1,
tdp-1, and
smn-1. We are examining the motor neurons in C. elegans mutants of these genes to look for axonal degeneration phenotypes that may be linked to MNDs.