Grant: Operating Grant

Motoneuron diseases such as amyotrophic lateral sclerosis (ALS) start by impairing movement and ultimately can cause death due motoneuron loss. While suppression of cell death has been the major but so far largely unsuccessful target for therapeutic discovery, prevention of pre-clinical loss of motor function is a potentially more effective approach. Recently, the proteins TDP-43 and FUS have been discovered as the major constituents of cellular inclusions from the spinal cord of ALS patients. Normally these proteins regulate transcription in particular of synaptic genes, whereas their mutations cause ALS and other disorders. We hypothesize that these mutated RNA processing enzymes lead to pre-clinical synaptic dysfunction, making the synapse a prime target for therapeutic development for these as yet untreatable diseases. However, synaptic defects have not been characterized for these new disease genes. We have therefore developed simple zebrafish models that are amenable to powerful synaptic and genetic analyses, including chemical genetic drug screening that has identified potential synaptic therapeutics with one of our compounds being tested on patients. A recent explosion in the genetics of motoneuron diseases has indicated that many of the genes causing the same familial disorder are also implicated in other disorders as well. Rather than acting individually, we will test the hypothesis that these genes may interact in a genetic network and that defining the network will reveal novel targets for therapeutic development. Characterizing these genetic and synaptic interactions requires multigenic analyses with in vivo models of motor function such as are possible in the zebrafish. This project will explore genetic interactions between mutated human genes expressed in zebrafish and will develop new pharmacological approaches by studying the role of calcium channels and their drugs of action on spinal cord neurons.