LRRK2: It’s Not All About The Neurons
While some forms of PD are due to mutations in single genes inherited from a parent, these cases only account for about 5-10% of total PD cases. The remaining 90-95% of subjects who develop PD have what is called sporadic or idiopathic PD (iPD). Because we haven’t completely figured out what causes iPD and because it has been estimated that heritable traits contribute up to 70% of risk for the development of iPD, we can study the monogenic forms of PD to gain insight into the disease and its progression. The most common genetic mutations that lead to the development of PD are in a protein called leucine-rich repeat kinase 2 (LRRK2). The clinical symptoms of LRRK2-related PD are very similar to those of iPD and research focusing on LRRK2 can be used to inform future research studies for iPD. We have yet to determine the physiological function of LRRK2, but it’s likely that the protein is acting with different functions depending on the specific cell in which it is expressed. The primary function of LRRK2 in a neuron is probably different than its function in an immune cell. Because of this, there are many different avenues of research to study to understand its underlying role in the pathophysiology of the disease.
There is now a wealth of evidence linking immune and inflammatory processes to iPD and we know that LRRK2 is highly expressed in cells of the immune system. Our studies have found that individuals with iPD have an increased amount of LRRK2 protein in their immune cells compared to age- and sex-matched healthy controls. In addition, iPD patients have higher levels of inflammatory proteins in their bloodstream. These findings are interesting because they support the idea that LRRK2 is an important player in iPD as well as in familial PD. It is possible that LRRK2 is playing an important regulatory role in the immune system and when mutated the cells become sick and less able to perform supportive functions that keep neurons healthy.
One known function of LRRK2 is its role as a kinase. A kinase is a specific type of protein that has the ability to turn other proteins to an “on” or “off” state—whether a protein turns “on” or “off” depends on a number of other factors in the cell. The fact that LRRK2 has this function is consistent with the idea that it may serve as a driver of the inflammation seen in iPD patients; but we still don’t truly know what comes first: the inflammation or the neuronal dysfunction. Is the presence of more LRRK2 protein contributing to the increased inflammatory state? Or is the inflammation in the patient contributing to an increase in LRRK2 protein expression? These are the critical questions need to be addressed in the next steps of research.
In order to use this information in the clinic, we must determine the actual function of LRRK2 within immune cells and parse out what it means for immune cell function to have higher levels of LRRK2. Because the mutated forms of LRRK2 have an increase in kinase activity, drugs that inhibit the kinase function of LRRK2 are being developed for clinical trials in familial PD and potentially iPD. These drugs have become increasingly more specific over time, an important characteristic because there are many proteins in a cell that have kinase function and it would be harmful to turn all of them off unintentionally. As we get more familiar with the function of LRRK2 in different cell types and its potential contribution to disease progression within the body, it will be possible to develop more therapeutic strategies targeting the function of LRRK2 in neurons and/or in immune cells for preventing or slowing down progression of familial PD and iPD.
Darcie A. Cook is a Doctoral candidate in Immunology and Molecular Pathogenesis working on her thesis project in the Tansey Lab. She currently works at the J. Sencer CDC Museum as an Education and Historic Collections Associate, and writes for the NIH BEST Blog.
Malú G. Tansey, PhD is a member of the WPC 2019 Program Committee, and also served as a committee member for the WPC 2016. She is a tenured Professor at Emory University School of Medicine in Atlanta.
Ideas and opinions expressed in this post reflect that of the authors solely. They do not reflect the opinions or positions of the World Parkinson Coalition®.