Preventing motor neuron death, and the axon and synapse loss that precede it, are the primary goals of research into amyotrophic lateral sclerosis (ALS). The molecular basis of selective vulnerability of motor neurones, the contiguous progression of the disease, and its age dependence are unknown. Neuromuscular junctions (NMJ’s) and their supporting axons are the largest components of a motor neurone (>95% of total cell volume). Since they are essential for motor neurone function, they must be protected. NMJ’s are thought to be the first neuronal compartment to degenerate, followed by axons, both in patients with sporadic ALS and in animal models of SOD1-dependent ALS. One approach to finding new neuroprotective methods is to seek modifiers of genes already known to offer partial protection to NMJ’s. We have been using ethylnitrosourea (ENU) mutagenesis in mice to seek novel mutations that enhance the protective effects of the axon-protective WldS gene, which slows down Wallerian degeneration after nerve injury. We are using a flexible technology, fibre-optic confocal microendoscopy (f-CoME) to screen for mutants showing strong synaptic protection. We have thus far trapped six phenodeviants, at least one of which appears to be a true dominant mutant passing on its characteristics in Mendelian fashion. We are also using the f-CoME technique to visualise and monitor synaptic degeneration in longitudinal studies of individual SOD1 and WldS mice.