Scientists usually use animal models when studying Parkinson's disease because these models mimic the disease well. They are limited, however, because they require either gene modifications or the injection of toxicants, which may not accurately represent how the disease occurs in humans.
But now, researchers at Texas A&M University have developed a model that uses a nontoxic way to generate the symptoms of Parkinson's: infection with a virus called Theiler's murine encephalomyelitis virus (TMEV), a natural pathogen in mice.
Their study is a game changer because it proves that a simple viral infection can trigger the exact brain damage and physical disabilities in animal models that are seen in people with Parkinson's disease — and it sets the stage for additional studies.
"The toxic-exposure models are useful for studying Parkinson's, but not all people who are exposed to chemicals go on to develop Parkinson's, so these models cannot show all the ways a disease as complex as Parkinson's actually begins or develops over time in people," said Candice Brinkmeyer-Langford , a neurogenerative disease expert with the Texas A&M University School of Public Health at Texas A&M Health .
Parkinson's affects more than 10 million people worldwide , making it second only to dementia among brain disorders. It destroys the cells that produce dopamine, a chemical essential for smooth body movement, leading to problems with balance and walking, tremors in the hands or fingers and overall stiffness, as well as mental or emotional distress.
Its origins are unknown, but for decades, experts have believed that the disease could be triggered by the brain inflammation caused by viruses—even those contracted decades earlier — as well as by a combination of a person's genetics and environmental factors. This idea recently was affirmed by Brinkmeyer-Langford and others at Texas A&M in the case of another devastating motor neuron disease, amyotrophic lateral sclerosis (ALS).
"Viruses are known to cause entirely different diseases based on a person's genetics," she said. "For example, the Epstein-Barr virus causes mononucleosis, but may also contribute to cancer or multiple sclerosis, and SARS-CoV-2 can attack the heart and brain as well as the lungs."
For this pilot study to test the validity of TMEV in studying Parkinson's, the researchers conducted experiments to measure the following:
- Brain cell infection and damage. One week after infection, the researchers confirmed that the virus had infected the dopamine-producing brain cells. At one month after infection, the dopamine-producing cells were destroyed in the site of viral infection. Dopamine-induced behaviors were compared between 13 infected animal models and 14 healthy control animal models after administering a dopamine-mimicking drug which produced a distinct movement pattern confirming dopamine neuron loss. This test confirmed that the virus caused a significant loss of these crucial dopamine brain cells over time.
- Speed and coordination. They compared 13 infected animal models against 14 healthy control animal models to track and measure their motor skills with a standard assessment called the pole test to determine if losing dopamine-producing cells causes the physical movement problems typically seen in Parkinson's patients. Animal models infected with TMEV had slower times to complete the test compared to the healthy control models, and this still was the case at week 20, when the study ended.
- Gait abnormalities. They used a specialized treadmill, which evaluated over 100 factors involved in walking, motor function and balance, to analyze how quickly and efficiently the animal models walked. The test confirmed that the virus caused physical weakness following the loss of dopamine producing cells due to viral infection, proving that the virus damaged the brain in a similar way as seen in Parkinson's patients.
Now that this innovative model has been proven, Brinkmeyer-Langford said future studies will include testing the TMEV model directly against standard, older animal models used in Parkinson's research, looking for early warning signs and biological markers for Parkinson's and analyzing how the body's immune response to a virus changes the brain.
"The clock is ticking, since the rapidly aging global population means the number of people with Parkinson's is expected to jump significantly ," she said.
Others involved with the study — all from Texas A&M — were graduate student Tae Wook Kang with the College of Veterinary Medicine and Biomedical Sciences (VMBS), Rahul Srinivasan with the Naresh K. Vashisht College of Medicine, and C. Jane Welsh with VMBS and the Department of Neuroscience and Experimental Therapeutics. They also are associated with the Texas A&M Institute for Neuroscience .
The study was published in Brain, Behavior, and Immunity-Health and was supported by the National Institute for Neurological Disorders and Stroke and a Texas A&M College of Veterinary Medicine and Biomedical Sciences Graduate Trainee Grant.
By Ann Kellett, Texas A&M University School of Public Health
