One of the most common inherited causes of Parkinson's disease (PD) is defect in the LRRK2 protein caused by changes, or mutations, of the LRRK2 gene. Our previous studies have shown that immune cells called macrophages are unable to carry a normal immune response without LRRK2. We now aim to explain how changes in the LRRK2 gene and protein influence immune response in people with Parkinson's disease. To do this, we will investigate whether macrophages with a PD-associated mutation in the LRRK2 gene also are unable to carry out the immune response. We will evaluate whether treating macrophages with LRRK2 inhibitors -- drugs that make LRRK2 dysfunctional -- has the same effect. Finally, we will study how pre-clinical models without LRRK2 or with LRRK2-associated PD respond to tuberculosis infection.
We hypothesize that macrophages with a PD-associated mutation in the LRRK2 gene, as well as macrophages treated with LRRK2 inhibitors, will be unable to carry a normal immune response. The lack of immunity will be determined by the cells' inability to properly respond to challenges, such as bacterial infection, insertion of foreign DNA into the cell, and damaged mitochondria (cells' energy powerhouses).
First, we will study how one PD-associated mutation in the LRRK2 gene affects the ability of macrophages to respond to bacterial infection, mitochondrial damage and insertion of foreign DNA into the cell. We will then assess the longevity and function of the immune system of normal pre-clinical models, models without LRRK2, and those with LRRK2-associated PD, all infected with tuberculosis. Lastly, we will test the impact of LRRK2 inhibitors on the immune response in normal macrophages and macrophages with a PD-associated mutation in the LRRK2 gene.
Impact on Diagnosis/Treatment of Parkinson's disease:
LRRK2 inhibitors are currently being developed for the treatment of LRRK2 PD. Our findings indicate that these drugs may have unintended effects on the body's ability to fight infection. It also is possible that individuals with LRRK2 mutations may be more vulnerable to infection. We will test these possibilities directly with LRRK2 inhibitors and indirectly with pre-clinical models infected with tuberculosis.
Next Steps for Development:
The next steps in this project would be to measure the immune response of monocytes -- another type of immune cells -- from the blood of people with LRRK2 PD and those with PD with an unknown cause.