Study Rationale: Mutations in LRRK2 are associated with inherited forms of Parkinson’s disease (PD). LRRK2 is a lysosomal protein that is produced in immune cells, such as macrophages. These cells are key players in the development of inflammatory responses, and the macrophages that reside in the brain — called microglia — play a role in PD pathogenesis. Our data suggest that macrophages with mutations in LRRK2 are dysfunctional, a finding that could have consequences for the pathogenesis of PD.
Hypothesis: We hypothesize that pathogenic mutations in LRRK2 alter lysosomal function in macrophages and the development of inflammatory responses.
Study Design: In this project, we will study macrophage lysosomal function in human and mouse macrophages genetically modified to express LRRK2 G2019S, the mutant LRRK2 that is most common in PD. To conduct these analyses, we will assess how the lysosomes are affected in these macrophages and the impact that mutant LRRK2 has on immune function.
Impact on Diagnosis/Treatment of Parkinson’s disease: Determining whether macrophages in individuals harboring LRRK2 mutations are dysfunctional is key to understanding how changes in the immune response contribute to PD. In addition, because cell death is linked to inflammation, these studies could identify new targets for preventing neurodegeneration.
Next Steps for Development: These studies will allow us to define whether macrophages with increased LRRK2 kinase activity (those harboring the G2019S mutation) are functionally altered. Similar studies could be performed in the future using macrophages with different mutations, not only in LRRK2 but also GBA.