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In an Animal Model of ALS, Researchers Report Peripheral Nerve Injury Spurs Earlier Disease Onset

Article In Brief

Researchers reported that a peripheral nerve injury in a transgenic rat model of amyotrophic lateral sclerosis generated an inflammatory cascade in the spinal cord that precipitated earlier onset of the disease.

New evidence from transgenic rats with the human gene that causes amyotrophic lateral sclerosis (ALS)—superoxide dismutase-1 (SOD1)—suggests that a peripheral nerve injury can speed up the ALS disease process, a finding that may have implications for some ALS patients.

Only about 2 percent of ALS patients have familial disease linked to the SOD1 mutation. The scientists from the University of Illinois at Chicago found, however, that in the ALS animal model, a crush injury set in motion an inflammatory cascade—with enhanced glial activation—an immune response observed in studies of sporadic ALS.

“For those who diagnose and treat ALS patients, it seems we all have anecdotal evidence of the patient who just happened to have an injury in the same limb where the ALS disease first started. Many of these folks were quite fit and athletic,” said the senior author of the study, Jeffrey A. Loeb, MD, PhD, the John S. Garvin chair, professor, and head of the department of neurology and rehabilitation at the University of Illinois at Chicago. The study was published in the April issue of Neurobiology of Disease.

There seems to be an increase in ALS among professional athletes and soldiers, Dr. Loeb said, and both groups have a higher risk for peripheral nerve and head injuries. “I see this pattern in a subset of my patients, and so have many of my colleagues. I wanted to understand whether or not this was just a coincidence.”

Dr. Loeb added: “Even though we only studied rats with the SOD1 mutation, the concept may be more generalized such that if you have a known mutation or a genetic background that predisposes you to get ALS, there is a strong possibility that how you live your life or what you are exposed to can initiate the disease process.”

The puzzle in ALS is that the symptoms are so variable. The disease starts in the upper body for some and the lower limbs for others. No one knows why. “There has to be an environmental contribution,” Dr. Loeb said.

Study Design, Findings

To test that thesis, Dr. Loeb and his colleagues used a rat model with the human SOD1 mutation to assess whether peripheral nerve damage may play a role in starting and perhaps accelerating the ALS disease process.

“Is it possible that injuries to the nerves and muscles send an unwanted signal to the spinal cord to push the limits in vulnerable people and ignite an inflammatory response that starts the disease process?” asked Dr. Loeb. “It would be pretty profound if there is such a relationship.”

The researchers collaborated with the hospital's orthopedic surgeons for help in developing a sciatic nerve crush injury. They exposed and pinched the sciatic nerve that feeds the leg and all three branches were crushed around the mid-thigh in the rats.


“Is it possible that injuries to the nerves and muscles send an unwanted signal to the spinal cord to push the limits in vulnerable people and ignite an inflammatory response that starts the disease process? It would be pretty profound if there is such a relationship.”


The experimenters did not know the genotype of the rats they were assessing. They compared functional outcomes following crush injuries in healthy wild-type rats, injured SOD1 rats, and SOD1 rats with no damage to the sciatic nerve. The rats were ten weeks old when they suffered the injury. Functional recovery measurements were performed on each animal. In wild-type rats with the injury, the animals dragged their hind legs for a few weeks and then began to walk normally; they completely recovered by five weeks. The injured SOD1 rats dragged their foot on the ground for three weeks and showed some improvement by five weeks but never fully recovered to their baseline levels that were measured a week before the crush injury. By this time, the other leg was showing signs of weakness.

The SOD1 rats that were injured showed signs of weakness in tests of hind limb strength at about one-week post injury (at 11 weeks of age) compared with 15 weeks (25 weeks of age) in the animals that had not been exposed to a nerve injury.

The disease started a month earlier than it would have without a nerve injury, said Dr. Loeb. The four injured SOD1 rats reached the end stage of the disease by a mean of 36.25 weeks compared with their three SOD1 littermates who lived on average to 42.33 weeks. The numbers were too small to reach statistical significance.

What was striking was the spinal cord's inflammatory response to this single injury, said Dr. Loeb. Pathological exams of the ventral horn showed that the injured SOD1 rats had a marked increase in inflammatory cells that essentially engulfed all the injured motor neurons. The crush activated microglia. The scientists took measurements of microglia at several points throughout the trial and watched as it increased and then came down. After microglia grew quiet, a second wave of astroglia arrived in the ventral horn. By this time, the diseased motor neurons had lost half of their synaptic connections. (They measured SOD1 expression, glial reactivity, and the synaptic integrity of motor neurons by testing spinal tissue over several time periods.)

“Microglia are known to prune synapses off neurons,” said Dr. Loeb. The motor neurons are useless without their connections. The injured SOD1 animals didn't live as long as SOD1 rats without a crush injury, he noted.

Dr. Loeb added that the research team observed an overexpression of mutant SOD1 protein in the ventral spinal cord in the injured SOD1 animals compared with the non-injured SOD-1 animals, which could have been the cause of this increased inflammatory response.

These findings in rats don't prove that there is a similar process underway in ALS patients, even in those rare families with an SOD1 mutation. But, Dr. Loeb said, “it does point to a pathological process triggered from the outside that spreads to the inside of the central nervous system and both initiates and leads to the spread of the disease from the initial site—specifically, a heightened and prolonged inflammatory response that leads to synaptic loss and motor neuron degeneration that spreads to adjacent, uninjured neurons.”

“It is a combination of a genetic vulnerability and an environmental insult. I think we need to address both risks in our patients, particularly if they have a known genetic risk,” he added.

The investigators are continuing their studies with this model system to see whether blocking the spread of this overactive glial response in the SOD1 rats can change the course of their disease—using a peripheral nerve injury as a new model to start the clock ticking and screen for new treatments. The group is also looking more closely at patients with a focal disease onset, who, even years earlier, suffered from an injury in the same region of the body where the ALS started.

Expert Commentary

“This is an important study because it demonstrates the importance of anatomical and local factors in ALS neurodegeneration,” said John Ravits, MD, professor of clinical neurosciences at University of California, San Diego. “Animal and cellular models mostly study mechanisms of neurodegeneration in two-dimensions: molecular and cellular changes over time. But we know from patients the problems are three-dimensional with cellular changes over time and space.”

“The propagative properties of key disease proteins including SOD1 as well as tau, TDP-43, and synuclein are among today's hottest topics in neurodegeneration,” he continued. “The study significantly contributes to the conversation by demonstrating the phenomenon in vivo, showing the potential role of retrograde signaling from the periphery into the central nervous system and the potential triggering role of injury and inflammation. It provides an important model for dissecting the molecular and cellular events at an anatomic level and contributes to our understanding of the complex mechanisms.”

Another ALS researcher had a different view of the new study. “There is no evidence that trauma causes ALS in the absence of genetic mutations or susceptibility genes,” said Stanley H. Appel, MD, FAAN, co-director of Houston Methodist Neurological Institute and chair of the department of neurology and the Peggy and Gary Edwards distinguished chair in ALS at Houston Methodist Hospital. “There is evidence that trauma can exacerbate ALS. And that is what these investigators showed: an axonal crush in SOD1 animals decreased the likelihood of recovery in that limb.”

“We see patients who undergo surgery and have significant progression of their disease,” he added. “We see this a lot. But there is insufficient evidence that you can get injured and the trauma will trigger ALS.”


Drs. Loeb, Ravits, and Appel reported no competing interests.

Link Up for More Information

•. Schram S, Chuang D, Schmidt G, et al. Mutant SOD1 prevents normal functional recovery through enhanced glial activation and loss of motor neuron innervation after peripheral nerve injury Neurobiol Dis 2019; 124:469–478.
•. Liu J, Allender E, Wang J, Simpson EH, et al. Slowing disease progression in the SOD1 mouse model of ALS by blocking neuregulin-induced microglial activation Neurobiol Dis 2018; 111:118–126.