Objective/Rationale:
Mutations in the LRRK2 gene are the most common known genetic risk factors for Parkinson's disease. Although we know that these mutations can cause Parkinson's disease, the physiological function of the LRRK2 protein (genes encode proteins) remains a mystery. However, a hint of the LRRK2 function emerged from genetic studies in people with leprosy, a chronic infection caused by Mycobacterium leprae. They found that LRRK2 is associated to susceptibility to infection with M. leprae. The aim of this project is to find out if LRRK2 participates in the immune response to mycobacteria.
Project Description:
We will use a wide range of cellular and pre-clinical models of mycobacterial infection combined with methods of LRRK2 manipulation such as pharmacological inhibition and gene knockdown/knockout. First, we will evaluate the impact of pharmacological manipulation of LRRK2’s activity and LRRK2 loss of function on the infective process of Mycobacterium tuberculosis in cellular models. Second, we will investigate whether the loss of LRRK2 in knockout models alters the susceptibility to infection by M. tuberculosis.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Understanding the physiological roles of LRRK2 has the potential to shape our view of its role in Parkinson’s disease as well as our approach to targeting LRRK2 as a means to developing a therapy.
Anticipated Outcome:
At the end of the project, we will know if LRRK2 is involved in the immune response to mycobacteria.