The LRRK2-WAVE2 Interaction: Immune-mediated Phagocytosis in Parkinson’s disease
University of Ottawa
Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It’s cause(s) are predominantly unknown, but exposure to harmful environmental factors (toxins or infections) can increase an individuals’ risk of developing PD. Additionally, a portion of PD cases are caused by mutations in specific genes, such as LRRK2. Unfortunately, understanding exactly how mutations in LRRK2 or exposure to harmful environmental factors can lead to PD is unknown. Recent studies show that LRRK2 plays an important role in the body’s immune cells. Our bodies have immune cells in both the peripheral and the central nervous system. These cells clean up unwanted debris, damaged cells and they fight off agents that can harm the body. However, in the process of cleaning up and disposing of these unwanted elements, and if they are over-activated, immune cells can also cause unintentional collateral damage to the surrounding tissue. Therefore, using immune cells from mice that have healthy or mutant forms of the LRRK2 gene, we will explore the effect of LRRK2 on the function of immune cells in the body. We are currently exploring the various activities of these cells and are testing for compounds that can target their function.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
There are very promising aspects to this proposal. Firstly, the immune system response in Parkinson’s disease has been observed, but generally considered a secondary consequence of disease. However, we are exploring whether the immune system can actually contribute to the development of PD, giving us new pathways and targets. We are also identifying immune alterations that are readily detectable and which can be exploited for high-throughput compound screening. Lastly, since LRRK2 is: the most common genetic cause of PD, found in sporadic cases, and is clinically indistinguishable from idiopathic PD – our findings may be applicable to the general population.
We expect to fully characterize the functions of the immune cells with LRRK2 to test whether candidate compounds can act on it. Current therapeutics are employed once clinical symptoms have started and they do not halt or slow disease progression. However, with a validated target mechanism, we can assess its involvement in causing or advancing disease and can test early interventional strategies that may slow its course. Working with LRRK2 encourages pharmaceutical developers to continue pursuing avenues to create and deliver LRRK2 acting drugs to the central nervous system, since existing compounds do not cross the blood-brain barrier.
A genetic mutation in the leucine-rich repeat kinase 2 (LRRK2) gene confers a risk for development of Parkinson’s disease (PD). The study of the LRRK2 gene is highlighting the importance of potential gene-environmental interplay. This is quite intriguing since it has been long debated whether neuro-inflammation is causative or consequential in PD. Our project is part of our effort to elucidate the normal functions of this gene in immune cells. Previously, we found that LRRK2 pathogenic mutant (LRRK2 G2019S) hyper-activates immune function called phagocytosis through up-regulation of WAVE2, which finally induces neuronal death. Here, we found that rPTH1-34, an FDA approved hormone, inhibits WAVE2 and subsequently reduces hyper activated phagocytosis. We also revealed that downregulation of WAVE2 by rPTH1-34 protects dopaminergic neuron from LRRK2 pathogenic mutant mouse model. These events contribute to neurodegeneration in models of Parkinson’s disease. These findings reveal a potential biological target for therapeutic development. To substantiate this claim, we are currently studying the usage of rPTH1-34 to ameliorate disease progression in both familial or non-familial PD.