Researchers Create Mouse Model to Mimic Parkinson’s Disease

Researchers from the Jan and Dan Duncan Neurological Research Institute (NRI) at Texas Children’s Hospital and Baylor College of Medicine have recently made an important advance in the research and modeling of neurodegenerative diseases. They have created a mouse model that reproduces the early non-motor symptoms and motor difficulties of Parkinson’s disease in a way that directly mimics the disease in many patients.

This research, published in the Proceedings of the National Academy of Scienceswas led by Dr. Huda Zoghbi, professor emerita at Baylor, director of the Texas Children’s NRI, and a Howard Hughes Medical Institute investigator. Zoghbi’s research is distinguished by the use of precise models of human neurological disorders to advance our understanding of disease.

Parkinson’s disease is a devastating neurological condition that affects approximately 6 million people worldwide each year, including approximately 1 million Americans. According to the Parkinson’s Foundation, this number is expected to increase by 20% in the United States by 2030. There is no cure for Parkinson’s disease, making it all the more important to research and develop treatment strategies.

The most well-known symptoms of Parkinson’s disease are associated with motor dysfunction such as tremors and balance problems that appear later in life, but Parkinson’s patients may experience gastrointestinal problems such as constipation and/or loss of smell about 20 years before being diagnosed with the disease.

The exact cause of Parkinson’s disease remains largely a mystery. Scientists believe that a combination of genetic and environmental factors is most likely to cause or worsen the disease. A genetic predisposition, such as mutations in certain genes like SNCA (α-synuclein), and other factors such as age, exposure to pesticides or other chemicals, may all play a role in the development of Parkinson’s disease.

Animal models are essential for studying human diseases. However, one of the main challenges of using model systems is that they often do not accurately reflect human disease. The limitations of models are particularly important when studying late-onset neurodegenerative diseases, given the slow progression of these diseases over several decades.

“The challenge with using mice to model Parkinson’s disease is that even though the mice may be old, their neurons, even when they’re two years old, aren’t exactly as stressed as human neurons that have been around for decades,” Zoghbi said. “Sometimes mice engineered to carry the same human mutation don’t show the same characteristics that are seen in humans, probably because the disease takes a long time to manifest.”

More than 25 years ago, scientists established that mutations in the SNCA gene lead to an accumulation of the protein α-synuclein, causing the loss of dopamine-producing neurons in the midbrain, a hallmark of Parkinson’s disease. As a result, several mouse models overproducing mutant forms of α-synuclein have been generated.

Although these models recapitulate neurodegeneration and some features of motor dysfunction, the mice did not exhibit all of the features seen in humans with Parkinson’s disease.

For their model, Zoghbi and Dr. Youngdoo Kim, a postdoctoral associate in the Department of Molecular and Human Genetics, used CRISPR-Cas9 technology to introduce a known SNCA mutation that causes Parkinson’s disease, called G51D, into the SNCA gene in mice.

Kim explains that simply introducing the mutation into the native gene allows the “gene to be expressed at the right time, in the right place, and in the right dosage” because the gene is produced normally, just as it would be in a human carrying the mutation.

When Kim characterized the mice, he found that this G51D mouse model completely recapitulated the progression of Parkinson’s disease in a manner similar to how it develops in humans. The mice begin to show early signs of Parkinson’s disease in their olfactory system and intestines (a result of α-synuclein accumulation) as early as 3 months of age.

Motor difficulties and loss of dopamine-producing neurons do not appear until 8 to 10 months of age, when G51D mice have problems walking and balancing and suffer from the same neurodegeneration as humans.

The fact that non-motor symptoms appear much earlier than typical motor difficulties underscores the importance of screening for smell loss and constipation in aging adults to aid in early detection of the disease.

“The G51D mouse model represents the most accurate model of Parkinson’s disease available today. The fact that early human symptoms are not represented by other models means that these mice can be used to monitor biological changes during Parkinson’s disease progression to better understand the sequence of molecular events leading to brain dysfunction,” Kim said.

“This new model will be a valuable tool to help identify new biomarkers of Parkinson’s disease and to test a range of treatments and non-pharmacological interventions that could modify the course of Parkinson’s disease progression and, one day, perhaps even prevent the disease. The Zoghbi lab will make this model available to any interested researcher.”