Mouse models of ALS: Past, present and future.

Genome sequencing of both sporadic and familial patients of Amyotrophic Lateral Sclerosis (ALS) has led to the identification of new genes that are both contributing and causative in the disease. This gene discovery has come at an unprecedented rate, and much of it in recent years. Knowledge of these genetic mutations provides us with opportunities to uncover new and related mechanisms, increasing our understanding of the disease and bringing us closer to defined therapies for patients. Mouse models have played an important role in our current understanding of the pathophysiology of ALS and have served as important preclinical models in testing new therapeutics. With these new gene discoveries, new mouse models will follow. The information derived from these new models will depend on the careful construction and importantly, an understanding of the capabilities and limitations of each of the models. The genetic discovery in ALS comes at a time when genetic engineering technologies in mice are highly efficient through CRISPR/Cas9 and can be applied to a wide array of genetic backgrounds. New mouse resources in the forms of the Collaborative Cross and Diversity Outbred panels provide us with unique opportunities to study these mutations on diverse genetic backgrounds, and importantly in the context of a population. This review focuses on the mouse models of the past and present, and discusses exciting new opportunities for mouse models of the future.