Stay on target
While the genetics of amyotrophic lateral sclerosis largely remains a mystery, new gene-editing techniques are helping to uncover details of ALS.
Researchers at the Stanford University School of Medicine used CRISPR-Cas9 technology to identify specific genes that help protect against a toxic disease-causing protein.
ALS, also known as motor neurone disease or Lou Gehrig’s disease, erodes muscle function and impairs the brain’s ability to communicate with the body.
A genetic abnormality, known as a hexanucleotide repeat, in the C9orf72 region interferes with normal production of proteins.
“In a healthy person, you might see 10 to 20 of these DNA repeats,” graduate student Michael Haney explained. “But in ALS, they expand to hundreds or even thousands of repeated segments, and that’s the template for the production of these toxic proteins.”
Simple tasks like speaking, swallowing, or breathing becomes increasingly difficult, and, eventually impossible.
“These toxic protein aggregates are what’s likely driving the pathology in the disease,” Stanford professor Aaron Gitler said in a statement. “But no one really knows how they cause neuronal cell death.”
Instead of separately interrogating every gene in the human repository, they used new technology to produce “gene knockouts.”
Think about it: If you pinpoint and remove a gene, and the ALS protein repeats are no longer toxic, you know the absence of that gene protects neurons against degeneration—and vice versa.
“And perhaps more importantly, it may be a potential drug target,” a Stanford University press release said.
In the end, researchers found some 200 genes that, when knocked out, protected the cell, or made it more vulnerable. Two subsequent knockout rounds helped narrow down the results.
“I think it’s a really exciting application for CRISPR screens, and this is just the beginning,” Bassik said.
He and Gitler are teaming up to use this approach on other neurological diseases, including Huntington’s, Parkinson’s, and Alzheimer’s.
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