Northcott Neuroscience Laboratory Projects

Motor Neuron Disease Zebra Fish Models

I Whiteman, C Winnick, D Goh, A Laird, J Solski, I Blair, N Cole, G Nicholson

Neuropathological hallmarks of the disease amyotrophic lateral sclerosis (ALS) include aggregation of the proteins Fused in Sarcoma (FUS) and TDP-43, two related, predominantly nuclear proteins. The discovery of ALS causing mutations in the genes encoding these proteins, FUS and TARDBP respectively, by members of our team and others, has provided compelling evidence for an important role of these proteins in the pathogenesis of ALS.

Our team has created in vivo models of ALS in zebrafish, an animal model that is becoming widely regarded for its advantages in both developmental biology and human disease research. By generating transgenic zebrafish lines expressing specific human FUS or TARDBP mutations identified in ALS families, we are able to investigate in vivo the role of mutant FUS and TDP-43 in the pathogenesis of ALS.

Preliminary studies suggest that our transgenic zebrafish recapitulate some of the ‘proteinopathic’ features and motor neuron defects observed in human ALS, including mislocalization and aggregation of FUS, formation of stress granules and aberrant motor neuron branching. We now aim to investigate the impact of these abnormalities on motor control and behaviour. Further, we will use these transgenic lines to test drug therapies. This research is funded by the Snow Foundation.