A large, multidisciplinary team led by researchers from Texas A&M University has made a potentially game-changing discovery about the development of devastating motor neuron diseases like amyotrophic lateral sclerosis (ALS).
The team identified a specific type of mouse — the CC023 strain — that responds to a viral infection in a way that looks remarkably similar to humans with ALS.
"This is exciting because this is the first animal model that affirms the long-standing theory that a virus can trigger permanent neurological damage or disease — like ALS — long after the infection itself occurred," said Candice Brinkmeyer-Langford , a neurogenerative disease expert with the Texas A&M University School of Public Health .
The CC023 strain provides a unique "test track" for scientists to identify early warning signs for ALS through the biomarkers that appear after infection, she said. In addition, it could lead to testing and new treatments, especially for sporadic ALS, which makes up more than 90% of cases and is not hereditary.
For its study , which was published in the Journal of Neuropathology & Experimental Neurology, the team used Theiler's murine encephalomyelitis virus (TMEV) to infect five strains of genetically diverse animal models. They then assessed how the unique DNA of the different strains affected their responses to the virus during acute, subacute and chronic phases of infection.
The researchers tracked changes over time and between the different mice strains using five methods:
- Comparing spinal cord inflammation between infected and healthy mice at different times.
- Comparing levels of inflammation among the five mouse strains.
- Determining if higher levels of inflammation were directly linked to more paralysis and other severe physical symptoms.
- Measuring the amount of virus present.
- Testing whether higher amounts of the virus led to higher levels of spinal cord inflammation.
There were four key findings:
- Early damage. Within the first two weeks, all mouse strains showed nerve damage in the lumbar spine. Some strains showed signs of illness as early as four days after infection.
- Muscle loss. Over the long-term phase of the illness, the virus was eliminated from the spinal cord, but the CC023 mice experienced permanent muscle wasting.
- ALS similarities. The CC023 mice showed physical symptoms and lesions very similar to those seen in humans with ALS.
- Immune response. While the immune cells of the mice were very active early on to fight the virus, this activity stopped once the virus was cleared.
In short, the initial viral infection spread and infected the lumbar spinal cord early on, triggering an immune reaction, lesions and signs of illness. The virus was cleared over time, but the lesions and clinical symptoms persisted, and in the CC023 strain these signs resembled ALS-like disease.
The bottom line, according to Brinkmeyer-Langford? Genetics matter.
"This study gives us a new way to understand the various types of damage caused by a viral infection to the spinal cord and its nerves and muscles, especially since we now know that the initial viral infection triggers lasting, damaging reaction in susceptible individuals," she said.
This work was supported by the National Institute for Neurological Disorders and Stroke, National Institute for Environmental Health Sciences and a National Science Foundation Graduate Research Fellowship.
Others involved with the study were lead authors Koedi S. Lawley and Tae Wook Kang , as well as Raquel R. Rech , Aracely A. Perez Gomez , Katia Amstalden , Yava Jones-Hall , C. Jane Welsh and Colin R. Young , all with the College of Veterinary Medicine and Biomedical Sciences, along with Raymond Carroll , with the College of Arts and Sciences and David W. Threadgill , with the College of Agriculture and Life Sciences, as well as Moumita Karmakar from the University of Wisconsin-Madison.
By Ann Kellett, Texas A&M University School of Public Health
