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CRISPR helps scientists track down potential therapeutic targets for ALS

Scientists have used genome editing to pinpoint genes that reveal information about ALS and may even protect against the degeneration of neurons.

Like many neurodegenerative diseases, the inner workings of amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) are largely cryptic. But new findings from a study out of Nature Genetics have drawn back the curtain on some of the molecular underpinnings of the disease. What's more, these findings could even help pinpoint new drug targets for ALS, too.

ALS degrades neurons that operate voluntary muscle movements -- patients who suffer from the disease become immobile and unable to talk, or even breathe, on their own. Scientists know that in the brains of these patients large clumps of anomalous proteins build up around healthy neurons, and as a result, the cells die off. What's less clear, however, is how or why this happens.

Aaron Gitler, PhD, and Michael Bassik, PhD, both geneticists and senior authors of the study, explored this question, investigating genes that could contribute to the disease's progression and toxicity. Graduate students Nicholas Kramer and Michael Haney also contributed to the work.

Using CRISPR-Cas9 gene editing technology, the collaborators probed human genes, hoping to find out if any genes either enhanced toxicity of the protein clumps, or protected against their harm.

As explained by our release:

Rather than separately interrogate every gene in the human repository, the researchers used a tactic called genome-wide screening, which harnesses CRISPR-Cas9 to alter the function of every single human gene simultaneously. In this case, they used the technology to produce 'gene knockouts,' targeting genes with a kind of molecular scissors that makes precise cuts, leaving them unable to carry out normal function.

The gene knockouts, Kramer explained, help the researchers spot genes that either enhance toxicity or prevent it: If you identify a gene and knock it out, and the ALS protein repeats are no longer toxic, then you know that the absence of that gene actually protects the neuron against degeneration. And perhaps more importantly, it may be a potential drug target.

Overall, the researchers found about 200 genes that affected the toxicity of the destructive proteins, one of which really caught their attention. The gene is called Tmx2 and is found in a compartment of the cell called the endoplasmic reticulum. When Tmx2 was knocked out, the effects were quite impressive:

... when depleted in mouse neurons in a dish, the cells survived nearly 100 percent of the time -- quite a jump, considering that the survival rate for normal neurons was 10 percent.

'We could imagine that Tmx2 might make good drug target candidate,' Haney said. 'If you have a small molecule that could somehow impede the function of Tmx2, there might be a therapeutic window there.'

Image by Shutterstock

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