For years, the cause of the genetic link between Parkinson’s disease, Crohn’s disease, and leprosy has largely remained a mystery. However, a recent U of T-affiliated research effort has made significant strides by demonstrating that the cause seems to stem from inflammation.
Dr. Bojan Shutinoski, the first author of the study published in Science Translational Medicine at The Ottawa Hospital, explained to The Varsity that the gene in question, LRRK2, has been previously studied in relation to Parkinson’s and neuronal function. Shutinoski worked with co-authors, including Dr. Juliana Rocha of U of T, to complete the study.
Parkinson’s is caused in part by a lack of dopamine, which is produced by some neurons. This would suggest that the gene influences the neurons’ health. However, the study is the first to link a mutation in the gene to the immune system’s function.
The mutation in question is named ‘p.G2019s,’ and was linked by the study to an increased risk for developing Parkinson’s disease, Crohn’s disease, and leprosy. The risk stems from the mutation’s ability to cause the immune system to become hyperactive during periods of infection, which leads to high levels of inflammation.
The study’s design
Mice carrying the mutation, as well as ‘wild-type’ mice without the mutation, were infected with Salmonella typhimurium — a strain of bacteria that can cause sepsis.
Another experiment in the study infected mutated mice with a virus limited specifically to the peripheral system — the nervous system outside of the brain and spinal cord — and the mice were then compared with wild-type infected mice.
The analysis demonstrated that mice expressing the mutation were better able to control infection with higher levels of inflammation than the wild-type mice. However, this inflammation can be damaging.
The impact of inflammation on disease development
Inflammation specifically leads to an increased production of reactive oxygen species (ROS) in the brain, which can damage cell structures in high concentrations. These species damage or even destroy the neurons that produce dopamine, strengthening the link to Parkinson’s.
According to Shutinoski, one unique discovery from this experiment is that even in mice infected with the bacteria that did not infect the brain, inflammation still had an impact on the brain.
Another interesting finding of this study is that female mice with the mutation were found to have higher levels of inflammation than male mice. Similarly, in humans, Parkinson’s generally affects more men than women.
However, when Parkinson’s in humans is linked to p.G2019s, the opposite is true, and women have higher rates of the disease. This correlates with the findings in mice, yet the differences between the sexes are still open questions in science.
Applications of the study
Shutinoski suggested two clinical applications from this enhanced understanding of LRRK2. Primarily, since the LRRK2 gene produces an enzyme named dardarin, there are specific inhibitors that could hamper its activity.
However, more work must be done to ensure that the inhibitors are exclusive to the enzyme — otherwise, inhibiting other similar enzymes could harm the immune system response. Additionally, the regulation of ROS production could yield positive results in patients with increased inflammation, as a decrease in ROS could lead to healthier neurons and more regular dopamine production.
There is still much to learn about LRRK2, Parkinson’s, and inflammation, and this study has opened up a wide range of questions for researchers to tackle in the future.
One final aspect of this study is that it was a collaborative effort across several research groups. The main group working with LRRK2 worked with Crohn’s researchers in the local area.
To Shutinoski, the teamwork of the researchers was crucial to the study’s success.
“Science thrives in collaboration,” he said. “Our paper is… proof that collaboration works.”
