The findings could explain why athletes and soldiers seem more prone to progression with the fatal disease.
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that disproportionately affects athletes such as the legendary New York Yankees first baseman Lou Gehrig.
A new study potentially linking the disease to nerve injuries suggests a possible reason why.
Athletes, as well as people serving in the military, are more likely to suffer nerve injuries. And in some cases, the muscle weakness characteristic of ALS has been observed to start at the site of an injury and slowly spread to the rest of the body.
That type of disease progression, known as “focal onset,” was recently replicated in an animal study led by researchers at the University of Illinois College of Medicine.
Their work could reveal new avenues for treatment and prevention of ALS, according to the study published in the journal Neurobiology of Disease
In the study, rats genetically engineered to develop ALS-like symptoms had an abnormal inflammatory response in the spinal cord when researchers inflicted a crush injury to the sciatic nerve in the leg.
The inflammation and other damage led to progressive muscle weakness throughout the body.
“Our results show that a single nerve injury, which is small enough that it only causes temporary weakness in normal animals, can start a cascade of inflammation in the spinal cord that initiates and causes the disease to spread in genetically-susceptible animals,” said Dr. Jeffrey Loeb, the study’s corresponding author and a professor and head of neurology and rehabilitation at the University of Illinois College of Medicine. “The ability to precipitate the disease through injury gives us a new animal model we can use to identify treatments for ALS that focus on stopping the spread of the disease after it first starts.”
Dr. Stanley H. Appel, chair of the Stanley H. Appel department of neurology and the Peggy and Gary Edwards distinguished chair in ALS at Houston Methodist Hospital, praised the research but emphasized that the findings show only that a nerve injury may exacerbate disease progression in animals that already have ALS.
“What it’s saying is that if you have trauma in a peripheral nerve it’s going to make your ALS worse not only in the [region] where the trauma was, but in a broader distribution that will spread,” Appel, who is also the co-director of the Houston Methodist Neurological Institute, told Healthline. “There is no evidence that injury triggers ALS.”
Appel said that the genetically engineered rats in the Illinois study would have developed ALS whether they had been injured or not.
Currently, there are no treatments that significantly slow or stop the progression of ALS.
The research was prompted, in part, by the case of a former University of Illinois soccer player who died of ALS before the age of 30, Loeb told Healthline.
“We’ve been getting calls from all over the world about cases of ALS with injury causes since the study was published,” he said. “We are now systematically going back to identify patients whose disease started with a focal point, even if it was an injury that occurred 15 or 20 years ago.”
Past research has shown that, like the lab animals in the Illinois study, genetics can play a role in predisposing certain individuals to ALS. One of these genes, called SOD1, was mutated in the study to make the lab rats more likely to develop ALS.
However, studies have shown a genetic link to the disease in only about one in 10 cases of ALS in humans, meaning the cause of the illness remains unknown in most instances.
“One of the big mysteries in ALS is why the disease starts in different places for different people,” Dr. Stephen Goutman, a neurologist and director of the ALS clinic at Michigan Medicine, the academic medical center of the University of Michigan, told Healthline.
Appel said that there is an ongoing debate among ALS researchers about whether the disease originates in peripheral neuromuscular junctions, or in the brain.
“The question is whether it is ‘top down’ or ‘bottom up,’” he said.
In the Illinois study, researchers compared the mutated rats to a control group of wild rats.
The wild rats recovered quickly from the imposed nerve injury to their legs, but the SOD1 group never recovered. Those rats also experienced weakness in their other leg, and exhibited high levels of prolonged inflammation.
In the spinal cord region associated with the injured neuron, inflammation also spread to adjacent neurons among the SOD1 rats. Elevated numbers of microglia cells also were observed in the region.
“This spread of inflammation could potentially explain how the disease spreads once it first starts from the site of injury,” Loeb said. “Microglia have many roles, but one role is to prune or eliminate synapses that connect one nerve cell to another. These connections are critical for normal functioning and for survival of neurons during development. Where there was increased inflammation and microglia in the spinal cord, we saw up to a two-fold reduction in the number of synapses.”
The resulting loss of connection among nerve cells also can lead to the death of adjacent cells.
“This chain reaction of cell death could be what causes the progressive spread of muscle weakness we see in ALS,” Loeb said.
Goutman said that Michigan researchers have also observed the over-activation of immune cells in ALS patients.
“The authors’ notion of gene and environment interaction is correct,” he said. “While we do not have a clear history of a nerve injury preceding ALS symptoms in persons coming to see us with ALS, we do believe these insults to the nervous system can be triggered by other environmental toxins and sources.”
The findings may be significant enough to suggest that people with a known genetic predisposition to ALS avoid contact sports and other occupations that carry a higher risk of nerve injuries, said Loeb.
The research also supports ongoing efforts to develop drugs that dampen the inflammatory response that can be triggered in the spinal cord by injuries in other parts of the body, he said.
The National Football League has paid hundreds of millions of dollars to families of former players who say injuries sustained in games resulted in ALS, Parkinson’s, or the progressive brain disease CTE.
Despite the legal settlement, however, Appel suspects that the underlying cause of the disease can be attributed to genetics, not injuries.
“If you don’t have a family history of ALS, the most likely explanation is that you have multiple susceptibility genes,” said Appel. “The genes load the gun and the environment pulls the trigger.”
Researchers say nerve injuries may trigger a systemic inflammatory response leading to the deadly disease ALS.
The study is the first to demonstrate an environmental role in disease progression.
The research could lead to preventive steps such as urging people at risk of ALS to avoid contact sports as well as treatments targeting the inflammatory over-response.