Columbia Researchers Create New Model of ALS

Mutations in more than 20 genes are known to cause amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, but much of what we know about the disease has been learned from mouse models with mutations in just one gene, SOD1, the first gene linked to ALS.

To help scientists gain a more complete understanding of ALS and how it can be treated, researchers in Columbia’s Motor Neuron Center have created new mouse models based on mutations in a recently discovered ALS gene called FUS.

About 50 different mutations in FUS can trigger ALS. Some mutations cause some of the most aggressive cases of ALS in children, while others lead to more frequently reported cases that begin around age 50.

The Columbia researchers created several mouse models with different human FUS mutations and looked at the effect of the mutations on motor neurons, the cells killed by the disease.

The models have many features of the human disease, says Neil Shneider, MD, PhD, director of the Eleanor and Lou Gehrig ALS Center, who led the research. “We see that the same motor neurons that deteriorate in patients also deteriorate in our models, and we see the same progressive loss of motor neurons over time, with more rapid progression in mice with mutations linked to juvenile ALS.”

The researchers have already used the mouse models to begin to unravel how FUS causes ALS. Though previous research suggested that mutated FUS may be inactive and the loss of FUS activity leads to disease, Dr. Shneider’s team showed that mutated FUS proteins are instead toxic to the motor neurons.

Screening for potential drugs to counteract FUS is already under way at the center.

It is too soon to tell if the cellular mechanisms that cause ALS in people with FUS mutations apply to other patients with ALS, Dr. Shneider says, “but we’re finding commonalities between FUS and SOD models and that’s exciting. ALS looks very similar from patient to patient, so we believe strongly that there are common mechanisms that will eventually lead us to better treatments for most patients.”

The research was published Feb. 4 in Nature Communications.