Generation of novel animal models of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an invariably fatal neurodegenerative disease that is characterised by rapidly progressive motor neuron death. The pathological mechanisms responsible for the disease remain elusive and effective therapeutics are yet to be identified. Given the inherent difficulties of studying neurodegenerative conditions, animal models that reflect disease characteristics are essential to investigate the aetiology of the condition. By furthering our understanding of the cellular mechanisms involved, potential biomarkers and therapeutic targets can be identified for diagnostic, monitoring and treatment purposes. Current animal models have provided limited insights into ALS pathogenesis and it is widely considered that no existing model of ALS adequately reflects the disease phenotype. Furthermore, therapeutics found to be beneficial in these models have so far failed to translate to human clinical trials. Therefore, there remains a need for novel animal models of ALS that better reflect human disease characteristics. This project sought to develop novel zebrafish and nematode worm models of ALS using a variety of strategies, based upon recently identified disease-linked mutations in the CCNF gene. These models will be the first to allow examination of the phenotypic effect of motor neuron, compared to ubiquitous expression of a human ALS-linked transgene and its zebrafish homologue, and a determination of the effect of a fluorescent tag on protein behaviour in vivo. Comparison of these models will allow selection of the optimal model for immediate functional studies and provide information that may be used to inform the design of future animal models of the disease.