Objective: The aim of this study is to elucidate disease-related metabolic and inflammatory pathways driven by LRRK2 G2019S in human iPSC-derived microglia.

Background: Parkinson’s Disease (PD) is the most common movement disorder, traditionally linked to dopaminergic neuron loss. However, increasing evidence highlights the contribution of microglial dysfunction to disease progression. Microglia are highly phagocytic, metabolically dynamic immune cells that rely on tightly regulated lysosomal function to maintain brain homeostasis. Upon stimulation, microglia undergo profound metabolic reprogramming, and lipid metabolism has gained prominence as an important determinant of their inflammatory phenotype. The G2019S mutation in LRRK2 is the most frequent cause of monogenic PD and leads to increased kinase activity. LRRK2 emerges as a critical regulator of endolysosomal pathways and appears to be abundant in microglia. While LRRK2 G2019S is known to disrupt neuronal function, its role in human microglia remains poorly defined.

Method: Induced pluripotent stem cells (iPSCs) carrying the LRRK2 G2019S mutation and the corresponding isogenic controls were differentiated into microglia using established protocols. Cells were then stimulated with interferon gamma (IFN-γ) in the presence or absence of MLi-2, a highly specific LRRK2 kinase inhibitor, and subjected to multi-omics analyses, including transcriptomics, metabolomics, lipidomics and proteomics, complemented by functional assays.

Results: Integrated analyses reveal LRRK2 kinase–dependent lipid storage defects and lysosomal lipid remodeling, including BMP, a key lipid of the endolysosomal system These findings coincide with alterations in lysosomal mass and acidification as well as increased expression and secretion of lysosomal stress-associated proteins including GPNMB. In addition, LRRK2 G2019S mutant microglia presented enhanced inflammatory activation with increased phagocytosis. Functional assays validate these findings.

Conclusion: Taken together these data show that LRRK2 G2019S hyperactivity reshapes microglial lysosomal and metabolic states, affecting their inflammatory response. Furthermore, the rescue effect we observe in the presence of MLi-2 highlights the therapeutic relevance of our work and suggests GPNMB as a key regulator of lysosomal function in LRRK2-PD microglia.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lrrk2-g2019s-drives-lysosomal-lipid-remodeling-and-inflammation-in-human-ipsc-derived-microglia/