A new study from Knight Initiative for Brain Resilience researchers may help explain an enduring mystery about amyotrophic lateral sclerosis (ALS): why the disease kills off some of the brain and spinal cord’s movement-controlling neurons while others show greater resilience.
As ALS progresses, more and more of those motor neurons degenerate and die. As a result, patients lose control of their bodies and become unable to breathe. Many people are diagnosed in middle to late adulthood, and most survive only three to five years after diagnosis.
“It’s a cruelly rapid disease,” said Olivia Gautier, a postdoctoral scholar in the lab of Knight Initiative researcher Aaron Gitler, the Stanford Medicine Basic Science Professor and a professor of genetics at Stanford Medicine.
Now, Gautier, fellow Gitler lab postdoc Jacob Blum, and their colleagues have taken a step toward better understanding ALS and pointed toward new ways to keep neurons resilient.
Their research, published June 23, 2026 in Cell, identified distinct molecular changes within motor neurons that precede their death. To the authors’ surprise, not all of those changes promoted neurodegeneration.
“Some of the molecular changes actually appear to be part of a protective response, but one that is happening too late and is ultimately insufficient to save the cell,” said Gautier. If those protective responses could be harnessed, she said, it could lead to new therapies for ALS.
Scientists already knew that a particular type of motor neuron, called alpha motor neurons, which trigger muscle contractions, are more vulnerable in ALS. But what made this cell type more susceptible – and what accounts for variations in susceptibility among alpha motor neuron subtypes – remained less clear.
To investigate what happens at a molecular level, Gautier’s team studied mice that had been genetically modified to express human SOD1-G93A, an ALS-associated form of the SOD1 gene. Mutations in SOD1 account for about 20 percent of inherited cases of ALS, and SOD1-G93A mice are widely used to model the disease. The researchers sequenced RNA from single cells in those mice, allowing them to see how the ALS mutation affected the molecular profiles of various types of motor neurons – and which profiles might signal that neurons would soon stop working.
That data revealed a subset of “disease-associated” alpha motor neurons that overproduced RNA molecules related to cell stress and death – in particular, a kind of cellular self-destruct called apoptosis. These same cells underproduced molecules related to cellular communication – such as the ability to grow and guide long nerve fibers called axons, form physical connections with other cells, and send chemical signals to other cells – including muscle fibers.
“These cells appear to be stressed alpha motor neurons that are also progressively losing core neuronal functions,” Gautier said.
The team also looked for changes in transcription factors – proteins that regulate which molecules a cell produces and how much of them it makes – in disease-associated motor neurons. Initially, the researchers had assumed any such changes would contribute to degeneration. Instead, they found an increase in transcription factors that “appear to be protective,” Gautier said. “That flipped our expectation.”
Additional experiments with spinal cord tissue from ALS patients suggested that similar molecular changes happen in humans, indicating that the findings in mice could be relevant to humans too.
The results suggest a possible path toward new treatments for ALS, but more research needs to be done, Gautier said. Next, the team plans to delete or suppress some of the genes related to cell death and dysfunction to see if those changes slow down disease progression in mice. Another approach might be to develop treatments to boost the protective responses the researchers saw, giving alpha motor neurons a better shot at survival.
“The goal here,” Gautier said, “is to make these vulnerable cells more resilient in disease.”