Small nerve injury may be the trigger for early manifestation or faster progression of amyotrophic lateral sclerosis (ALS) motor symptoms in the presence of disease-associated genetic contributing factors, a study with rats suggests.
The study, “Mutant SOD1 prevents normal functional recovery through enhanced glial activation and loss of motor neuron innervation after peripheral nerve injury,” was published in the journal Neurobiology of Disease.
ALS is a neurodegenerative disease that can have variable symptom onset, progressively affecting both upper and lower nerve cells that control body movement.
The degree of motor neuron involvement varies significantly among patients; it remains unclear why. Environmental factors may play an important role, contributing to the subset of nerve cells most affected at disease onset.
Studies have suggested that head injury or trauma could increase the risk for ALS development, which could explain the higher prevalence of the disease among war veterans and professional athletes. Still, these results are controversial, and contradictory findings suggest that moderate to severe traumatic brain injury can increase the risk of dementia but not of ALS.
Researchers at the University of Illinois at Chicago decided to further explore this issue in animal models of the disease. They used rats that had a genetic mutation in the SOD1, one of the 40 genes that have been associated with ALS development in humans, and compared them with healthy animals.
The researchers divided the animals into two groups, with one group undergoing an invasive procedure to induce damage to the sciatic nerve before any of the SOD1 animals had developed ALS-associated motor symptoms. They evaluated the impact of nerve injury in the symptoms’ progression.
Five weeks after the surgical intervention, the non-mutated rats were able to fully recover the function of the injury-affected leg. During the same time, SOD1 animals showed some improvement but were not able to fully recover. The team found that in SOD1 rats the uninjured leg was also functionally impaired compared to the uninjured leg in the non-mutated animals.
Evaluation of the animals revealed that the muscle strength in both injured and uninjured legs decreased earlier and faster in injured compared to uninjured SOD1 rats.
“These results show that a single peripheral nerve injury causes not only a failure to recover, but also precipitates a more rapid decline in function with mutant SOD1,” researchers said.
To better understand what could be contributing to the injury-induced severe progression of ALS symptoms, the researchers conducted a detailed analysis of the spinal cord of the rats at different time points.
They found that upon nerve injury, the resident immune cells in the spinal cord would be activated in order to help manage and resolve the damage. However, in SOD1 rats, these pro-inflammatory signals were sustained longer compared to non-mutated animals.
These rats also showed increased activation and spreading of a specific type of cell called astrocytes, which normally help nerve cells heal but have also been associated with the progression of ALS in humans.
Injured SOD1 rats experienced more severe neurodegeneration, with about two times the reduction of nerve cells’ communication structures compared to controls. This feature was triggered by the inflicted damage, as the nerve cells on the uninjured side had normal structures.
“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,” Jeffery Loeb, MD, PhD, the John S. Garvin Endowed Chair in Neurology and Rehabilitation in the UIC College of Medicine and senior author of the study, said in a news release.
“This chain reaction of cell death could be what causes the progressive spread of muscle weakness we see in ALS,” Loeb said.
The team believes that by using this strategy of induced nerve injury, it may become possible to explore new therapy that could prevent the early events that mediate ALS neurodegeneration.
“This model that coordinates the disease process at a precise time of onset could help develop therapeutics targeted at earlier stages of the disease and may translate better in clinical trials,” they said.