Though associated with only a small percentage of total Parkinson's cases, mutations of the LRRK2 gene are the greatest known genetic contributor to Parkinson's disease (PD). Researchers are striving to understand the mechanisms of disease related to this mutation because it is similar to that of sporadic (cause unknown) PD.
LRRK2 is present in cells throughout the body, including those of the brain and the immune system (which fights infection and has a role in inflammation that could contribute to PD). A recent study, funded in part by The Michael J. Fox Foundation (MJFF), examined the role of LRRK2 in the immune cells in blood of people with sporadic PD and healthy individuals.
Malu G. Tansey, PhD, associate professor of physiology and member of the Center for Neurodegenerative Disease at Emory University, was an investigator in the study. She spoke with us about the research, its results and what they mean for Parkinson's research and for people living with the disease.
MJFF: Thank you for taking time to speak with us, Dr. Tansey. How can better understanding of genetics deepen Parkinson's disease understanding?
Malu G. Tansey, PhD (MGT): The field has been focused on the effects of PD-associated gene mutations in neurons, but it's clear that there are many other cell types that express these genes, such as immune cells in the case of LRRK2. Understanding the genetic causes of PD can inform us about sporadic PD because the mechanisms underlying the pathways that are disrupted are likely to be similar.
MJFF: Can you tell us about the design and goals of the study?
MGT: The immune system - which is responsible for responding to every environmental trigger out there - is impacted by the aging process. Over time, the function and effectiveness of immune cells declines with age, which contributes to altered immune function and inflammation. Since LRRK2 is expressed in immune cells, we wanted to understand if aging or PD was associated with changes in LRRK2 levels that might make those cells more inflammatory or dysfunctional. So, we looked at immune cells in blood from people with Parkinson's disease between 50 and 85 years old, and age-matched healthy controls.
MJFF: And what did you find?
MGT: One of the surprising results was that, compared to healthy controls, people with sporadic PD had more LRRK2 protein in their major immune cell subsets. This may suggest that the body is trying to increase the amount of LRRK2 protein to regulate inflammation. The second big finding, however, was that many of the cell types that had higher LRRK2 also showed more inflammation. This might mean that even though there is more LRRK2, it's not enough to reduce or curb inflammatory responses.
MJFF: What does this mean for the Parkinson's community?
MGT: This research is consistent with other work that suggests LRRK2 may be important in regulating or curbing inflammation in immune cells. It moves us toward a better understanding of the inflammatory mechanisms that may contribute to Parkinson's, which could lead toward therapies to modify the onset or course of disease. In addition, confirming LRRK2's role and presence in immune cells in the blood means we could potentially use blood samples to measure the effectiveness of LRRK2-targeted therapies instead of having to perform more invasive procedures.
MJFF: What are the next steps to further this area of research?
MGT: The most common mutation of the LRRK2 gene is thought to result in too much phosphorylation (a process that turns protein enzymes on or off and alters their function) and LRRK2 kinase inhibitors are being developed by drug companies to dampen this down. We need now to look at how inhibiting LRRK2 kinase phosphorylation might change immune cell function. Ultimately, if LRRK2 function and LRRK2 kinase are important for immune cell function, then the inhibitors may help both neurons and immune cell function in people with sporadic Parkinson's. But based on our work, it will be important to understand the role of LRRK2 in immune cells to avoid potential collateral damage of these treatments on the immune system.
The Michael J. Fox Foundation is funding additional research at Emory University to analyze blood samples from people and mice with LRRK2 mutations to see how they compare to the results of this study, and to determine if LRRK2 kinase inhibitors impact immune cell function.
Read more about how the Foundation is speeding collective efforts to advance LRRK2 research.
Learn more about how you can get involved in LRRK2 research and see if you are eligible for Parkinson's Progressive Markers Initiative, the MJFF-led landmark biomarkers study.