Objective: To investigate the effects of pathogenic LRRK2 mutations on lysosomal function and phagocytic activity of microglia.

Background: The LRRK2 G2019S mutation is one of the most common genetic causes of  Parkinson’s disease (PD). Pathogenic mutations in LRRK2 have been shown to negatively impact lysosomal function in dopaminergic neurons, but there is emerging evidence that deleterious effects of LRRK2 mutations on immune cell function may additionally play a role in PD pathogenesis. LRRK2 is highly expressed in both microglia and peripheral macrophages. Furthermore, analysis of LRRK2 variants associated with PD has demonstrated that these variants are associated with microglia-specific changes in LRRK2 expression. Further work is needed to define how LRRK2 mutations may result in loss of normal microglial functions or the development of toxic microglial phenotypes in PD.

Method: Induced pluripotent stem cells (iPSCs) were generated from fibroblasts obtained from PD patients with LRRK2 G2019S mutations. Isogenic control iPSCs were produced by using CRISPR/Cas9 technology to correct the G2019S point mutation. These iPSCs were differentiated into microglia and the effects of the LRRK2 G2019S mutation on microglial phenotypes was examined in vitro. Live cell confocal imaging was used to measure microglial phagocytic activity as well as lysosomal protease activity.

Results: iPSC-derived microglia (iMGs) generated from PD patients harboring the LRRK2 G2019S mutation displayed changes in lysosomal morphology as well as differences in expression of lysosomal proteins compared to isogenic control iMGs. In addition, LRRK2 G2019S iMGs had reduced lysosomal protease activity. LRRK2 G2019S microglia furthermore displayed a time-dependent reduction in phagocytic delivery of multiple substrates to the lysosome, including myelin fragments and E.coli.

Conclusion: Human microglia harboring the pathogenic LRRK2 G2019S mutation display defects in lysosomal function accompanied by impaired phagocytosis of multiple substrates. Therefore, microglial lysosomal dysfunction is a potential non-cell autonomous mechanisms by which LRRK2 mutations could contribute to neurodegeneration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-role-of-lrrk2-in-regulating-microglial-activity-in-parkinsons-disease/