Zebrafish points the way towards a new therapy for ALS

25 October 2013

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative motor neuron disease for which there is currently no treatment. Using zebrafish as a model, genes were discovered that could play a role in the progression of ALS. The Laboratory of Neurobiology (KU Leuven & VIB, Belgium) has identified a molecule that could be a target for a future ALS treatment. This study was published in Nature Medicine.

Zebrafish as a model for ALS

Using a new zebrafish model for ALS, the research team of Wim Robberecht (KU Leuven & VIB, Belgium) searched for genes that improved the phenotype of the disease. The EphA4 receptor was identified as a genetic factor that modifies the clinical picture of ALS in zebrafish. Eliminating this receptor in zebrafish corrected the axonal phenotype in zebrafish, while blocking the receptor in the mutant SOD1 mouse model, an established model of ALS, resulted in a significant improvement of the animals’ life expectancy. The research also showed a correlation in ALS patients between the expression level of the EphA4 receptor and the age at which the patients are diagnosed. ALS patients who express a low level of the receptor develop the disease later in life in comparison to ALS patients who have large amounts of the receptor. It was also discovered that EphA4 prevented neurons from recovering after damage and that the cells that were most susceptible to ALS expressed high levels of the receptor.

Proof-of-concept study

This study is very promising and proves that small model organisms such as zebrafish can be valuable tools in the search for a therapy for ALS. It also shows that molecules that are essential for the development of the nervous system can play a role in the mechanism of neurodegenerative disorders in adulthood. Finally, the results suggest that blocking EphA4 modifies the course of the disease, meaning that the receptor may be a good target for a future ALS drug. There is still a long road ahead before such a drug will be available to patients.

Relevant scientific publication

This research was published in Nature Medicine (Van Hoecke A. et al., EPHA4 is a disease modifier of amyotrophic lateral sclerosis, Nature Medicine 2012; 18(9):1418-1422).