Through their behavioural analysis of genetically-modified worms, researchers from the MRC London Institute of Medical Sciences (LMS) have helped identify a potential drug target for amyotrophic lateral sclerosis (ALS). 

ALS is the most common form of motor neuron disease (MND). The inherited form of the disease is usually caused by mutations in a gene called C9orf72 which lead to the generation of small proteins known as dipeptide repeats (DPRs). These are thought to be toxic to cells, but further research is needed to understand why and how.  

Dr Andre Brown, Head of the LMS Behavioural Phenomics research group worked with others at the University of Chicago Medical Center and the Grossman Institute for Neuroscience to genetically alter C. elegans worms so they possessed the mutated C9orf72 gene. 

They found the mutated worms generated DPRs and displayed neurodegeneration, as expected. When they went on to study the animal’s movement, they used Dr Brown’s innovative imaging analysis tool, pioneered at the LMS. Through this, they could see that the worms had locomotor defects which are also seen in human ALS patients.

Having shown that the C9orf72-mutated worms displayed ALS-like disease, the team decided to take it one step further and genetically alter the worms again so that they would no longer produce large quantities of a specific DPR called poly-GA. Interestingly, Dr Brown’s group found these worms had better motility and a longer lifespan, which suggests poly-GA DPR contributes to ALS-like disease in worms. If this is also the case in humans, the molecular machinery that reduced the poly-GA DPR could provide a therapeutic target for ALS. 

“This is what we had hoped to see,” said Dr Brown, “Our imaging and behaviour quantification system was able to precisely identify locomotion defects in the worms. This is proof of concept and means we can expand our genetic library, creating worm models for a long list of underserved rare genetic diseases. I am excited to see how this progresses research in this field, and ultimately how we can translate what we find into the clinic to help patients in the future.”

An estimated 1700 people are diagnosed with ALS every year in the UK. It is a neurodegenerative disease, meaning the cells that make up the brain and nervous system begin to die. Symptoms include muscle stiffness, cramps and weakness in the limbs and life expectancy is usually two to five years after symptoms appear.

Generating animal models that display the same characteristics as human versions of illness can help scientists to unpick the complex molecular basis of disease. Dr Brown’s lab have shown their imaging and behaviour quantification system works and that this could have a widespread impact on finding treatments for a whole range of genetic diseases.