Study Rationale: Mitochondria-the powerhouses of the cell, contain their own DNA (mtDNA), which when damaged, can cause defects in mitochondrial function. Mitochondria can package mtDNA by into small compartments (VDIMs) that are shed from the mitochondria and then destroyed inside lysosomes- cell’s garbage disposal- which collect and degrade damaged cellular material. However, unregulated ‘leakage’ of this mtDNA from stressed mitochondria can lead to inflammation, a hallmark of Parkinson’s disease (PD). LRRK2, the gene most-commonly mutated in inherited forms of PD is highly expressed in immune cells and maintains lysosomal function. In this study, we will investigate how alterations in lysosomal function due to dysfunctional LRRK2 can lead to defective degradation of mtDNA and cause inflammation.
Hypothesis: We hypothesize that defects in lysosomal function due to dysfunctional LRRK2 will reduce the degradation of mtDNA inside VDIMs, which would lead to the development of inflammatory responses.
Study Design: We will use macrophages lacking LRRK2 or expressing the disease causing LRRK2 mutation and perform microscopy studies to investigate if compared to healthy cells, VDIM formation and mtDNA degradation is altered in these cells. Because contents of dysfunctional lysosomes can ‘leak’ into the cell and cause inflammation, we will assess if the presence of mtDNA in these lysosomes causes inflammation.
Impact on Diagnosis/Treatment of Parkinson’s disease: PD is associated with higher inflammation, but how this occurs is not clear. Defective clearance of VDIMs and mtDNA in the absence of normal LRRK2 function could be a key contributing factor for disease pathogenesis. Findings from the proposed studies could uncover new therapeutic targets in the VDIM pathway to regulate this inflammatory response.
Next Steps for Development: Findings from these studies will show a potential pathway by which LRRK2 mutations can contribute to inflammation. Next, we will extend these findings to relevant disease models using patient cells reprogrammed to form macrophage and microglia- the macrophages of the central nervous system. Lysosome function is impaired in additional PD associated mutations, not just LRRK2. Future work could also assess the role of VDIMs and mtDNA in causing inflammation associated with these mutations.