Scientists Discover Genetic Mechanism That May Explain How ALS Occurs

BALTIMORE — It’s been several years since the ice bucket challenge took the internet by storm. The social media campaign promoted awareness of the disease amyotrophic lateral sclerosis (ALS) and helped raise funding for ALS research. Despite the attention, there are still more questions than answers when it comes to the disease. Thankfully, an international research team led by the University of Maryland School of Medicine is making progress in the fight to figure out what causes ALS.  

ALS, also called Lou Gehrig’s disease, causes people to slowly lose the ability to use their muscles. Now, researchers have identified a specific gene that plays a major role in the development of ALS when this gene is mutated. This genetic mutation might also cause a form of dementia related to ALS.

The gene in question, UBQLN2, is normally responsible for disposing of “trash” from cells. ALS researchers have been suspecting mutations of this gene for quite some time, but they have not understood how mutations of this gene cause the disease until now.

“We mapped out the process by which ubiquilin-2 (UBQLN2) gene mutations disrupt an important recycling pathway that cells use to get rid of their trash,” explains Mervyn Monteiro, PhD, Professor of Anatomy and Neurobiology, at the Center for Biomedical Engineering and Technology (BioMET) at University of Maryland School of Medicine, in a university release. “Without this recycling, misfolded proteins build up in the nerve cell and become toxic, eventually destroying the cell. This destruction could lead to neurodegenerative disorders like ALS.”


First, the team re-engineered human cells and removed the UBQLN2 gene completely. They found that the cells’ recycling pathway completely broke down. Next, they inserted the normal gene or one of five mutations of the gene into the cells. They say only the insertion of the regular gene caused the recycling pathway to restart.

Researchers investigated the mechanism that genetic mutations use to disrupt this recycling pathway using a genetically-engineered mouse model. Mice with UBQLN2 mutations showed lower levels of a protein called ATP6v1g1, which helps cells break down their waste by pumping acid so the trash can be broken down.

Scientists studying other neurodegenerative diseases have discovered similar acid issues. “Our new findings are exciting because similar acidification defects have been found in Alzheimer’s, Parkinson’s and Down syndrome,” says Dr. Monteiro. “This suggests that restoration of the defect could have broad implications for not only treating ALS, but possibly other neurodegenerative diseases as well,” he concludes.

The study is published in Proceedings of the National Academy of Sciences.

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