Amyotrophic lateral sclerosis (ALS), one of the most common neuromuscular diseases, is a devastating incurable illness that leads to progressive paralysis and premature death, usually within 5 years of diagnosis. Drug treatment to slow ALS progression is limited to one drug, riluzole, which only prolongs survival by a few months. Very little is known about the molecular causes of ALS. The symptoms and progression of ALS are very similar in both sporadic and familial forms of the disease, leading to the notion that although there may be multiple initial causes, there could be convergence upon a common disease pathway.

Around 2% of ALS cases are due to mutations in the superoxide dismutase (SOD1) gene. SOD1 protects the body from free radical damage. Mice that are defective in SOD1 activity develop very similar symptoms to humans with either sporadic or familial ALS. Animal models in which SOD1 has been mutated have therefore been developed as vehicles to study both the onset and progression of ALS but, to date, only rodent models show the major phenotypes of ALS, limiting both the questions that can be addressed and the types of experiments that can be performed. Rodents are also impractical as in vivo models for high throughput whole-organism drug screens, which are essential for a disease where multiple tissues and cell types are affected.

The authors present a zebrafish model of familial ALS based on a common mutation, G93R, in familial SOD1-derived human ALS. They introduced the G93R mutation into zebrafish sod1 and generated transgenic lines expressing either G93R sod1 or wild-type sod1 protein. The highest expressing line had three- to fourfold more Sod1 protein in the spinal cord than normal fish. Fish overexpressing mutant Sod1 recapitulated the major phenotypes of ALS. Neuromuscular junction defects were detected during larval stages and were much more severe in adult animals. Adults also underwent motoneuron cell loss, muscle degeneration and early death, and showed decreased muscle endurance when subjected to a swim tunnel test. Maintenance of overall muscle integrity suggested that there was a neural, as opposed to muscular, defect.

This study provides a new vertebrate model of familial ALS that exhibits the major hallmarks of motoneuron disease. Zebrafish are an excellent organism for modeling neurological diseases as they have a conserved, yet simplified, vertebrate nervous system. They are particularly good for the study of motoneuron diseases, with accessible motoneurons that can be manipulated in vivo, making them highly relevant for performing cell-autonomy studies, electrophysiology and imaging. Importantly, this demonstration that zebrafish are a suitable model for ALS means that they can now be used both for large-scale genetic screening to identify ALS-causing genes, and as a platform for the development and screening of novel drugs.

2010