It has been suggested that defective synaptic transmission at the neuromuscular junction (NMJ) underlies the aetiology of motor neuron disease. However, our understanding of the regulation of synaptic transmission remains incomplete. In order to investigate this we identified 420 candidate synaptic regulators by combining MND genome wide association studies, gene enrichment at neuropil and hits from genome wide studies of pain and lethality in Drosophila. Using RNAi we specifically knocked down these genes in Drosophila motor neurons to identify new synaptic regulators through climbing behaviour. In parallel, we are investigating genes that modulate a MND phenotype (expression of TDP-43 in eye neurons). So far we have identified around 100 genes that have a role in motor neuron function. Gene ontology analysis of these hits suggests significant associations with microtubule organisation. We will now complete our screens and further examine candidate genes with synaptic assays including morphology and electrophysiology.