Researchers Identify New Gene Mutation Likely Involved in ALS Development

Joana Fernandes, PhD avatar

by Joana Fernandes, PhD |

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ALS gene mutation

Mutations in the UBQLN4 gene may contribute to the development of amyotrophic lateral sclerosis (ALS), according to recent research.

The study, “A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis,” was published in the journal eLife.

Over the years, researchers have identified numerous genes linked to ALS, but the list may not be complete.

“We know that many genes are involved in ALS and a major goal in the field is to identify as many of these genes as we can so we can uncover targets for treatment at the cellular level,” Brittany Edens, the study’s first author, said in a news release.

“We found that UBQLN4 gene variant interferes with a pathway involved in breaking down a certain protein called beta catenin, and the resulting accumulation of this protein leads to defects in the motor neuron structure. These defects likely make motor neurons vulnerable to progressive degeneration seen in ALS,” she said.

Using zebrafish, a model organism commonly used in research, the scientists demonstrated that variations within the UBQLN4 gene interfere with the proteasome, the mechanism responsible for the elimination of old and faulty molecules within neurons. This, in turn, induces several anomalies in the axons, an important component of the motor neurons.

However, treatment with a compound called quercetin, which can be found in many fruits and vegetables, reverted the motor neuron anomalies caused by UBQLN4 gene mutations by blocking the beta catenin signaling pathway, whose activity was impaired in zebrafish carrying these mutations. More studies are warranted to validate these findings in human patients.

“At this stage, it is unclear how many people with ALS have the UBQLN4 gene variant, and this will be important to determine,” said Yongchao Ma, the study’s principal researcher. “Another important next step will be to assess whether the disease mechanism we describe is common to other forms of ALS.”

“Another intriguing aspect of our study is the molecular link we have established between ALS and spinal muscular atrophy or SMA, which is a pediatric motor neuron disease,” Edens added. “We see a similarity in the increase of beta catenin, which causes defective motor neuron development. So even though the genes that cause ALS and SMA are different, they might share a common pathway that affects motor neuron structure and function.”