12 March 2018

Appeared in BioNews 941

Researchers have used genome editing to reveal genes that could be new therapeutic drug targets for the neurodegenerative condition amyotrophic lateral sclerosis (ALS). 

Findings from the study, published in Nature Genetics, provide new insights into the causes of ALS by revealing genes that either speed up or slow down disease progression. 

In many cases of ALS there is a known genetic element to the disease, often involving mutations in the C9orf72 gene. These mutations lead to abnormal repeats in a stretch of DNA, which in turn can create faulty proteins that form clumps, or aggregates, in the brain. Build up of these proteins cause death of brain and spinal cord cells, leading to muscle breakdown, paralysis and death. 

A large range of genes affect what happens to C9orf72 proteins. Some genes exacerbate the problem, making it much more likely that neurons will build up toxic levels of protein aggregates, the recent study reveals. Other genes have a protective effect. 

The authors aimed to find out what these genes were by using a new application of CRISPR/Cas9. The team combined the system with a genome-wide screen of more than 20,000 genes. The team were able to create knockouts of every gene in the human genome individually. When a gene appeared to influence protein aggregates, the team followed up by knocking out that gene in mouse neurons to analyse the effect. 

Out of 200 genes identified, a gene called TMx2 stood out for its role in cell death. The researchers found that mouse neuronal cells survived in almost 100 percent of cases if Tmx2 was knocked out, compared with just only 10 percent of cells expressing Tmx2.  

The exact role of Tmx2 protein in the cell remains unclear, but it’s thought to control other genes involved in the cell death process. 

‘Figuring out exactly what Tmx2 normally does in a cell is a good place to start – that would hint at what functions are disturbed when these toxic species kill the cell, and it could point to what pathways we should look into,’ said study author Nicholas Kramer.

If Tmx2 could be blocked, then it’s possible cell death would be slowed in ALS. 

‘We could imagine that Tmx2 might make [a] good drug target candidate,’ added study author Michael Haney. ‘If you have a small molecule that could somehow impede the function of Tmx2, there might be a therapeutic window there.’

The authors say the same approach could be used to explore progression of other neurological conditions (Huntington’s, Parkinson’s and Alzheimer’s) that share a similar pathology involving toxic proteins. 

‘I think it’s a really exciting application for CRISPR screens, and this is just the beginning,’ said Michael Bassik, another author of the study.