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Identifying novel LRRK2 substrates in mouse bone marrow-derived macrophages

ABSTRACT: LRRK2 is commonly mutated in Parkinson’s disease and has cell type-specific mechanisms of activation and function. In macrophages, LRRK2 is associated with lysosomes and is activated following lysosomal damage. However, the functional outcomes of clinically relevant pathogenic mutations in macrophages are unknown. Here, using primary mouse and patient-derived iPSC-derived macrophage (iPSDM) models of LRRK2-G2019S, we defined the substrates of LRRK2 after lysosomal damage. Using phosphoproteomics we found that LRRK2-G2019S and wild-type macrophages showed similar levels of Rab GTPases phosphorylation after lysosomal damage. However, the levels of pRab12 increased whereas the levels of pRab35 decreased in LRRK2-G2019S macrophages. Functionally, LRRK2-G2019S macrophages showed a deficit in lysosomal membrane repair that resulted in more cell death and increased apoptosis. Importantly, we recapitulated this phenotype in iPSDM from patients carrying the G2019S mutation, but not in isogenic control iPSDM. Altogether, we define here the signaling downstream of G2019S in macrophages and identify susceptibility to cell death after lysosomal damage as an important phenotype of this mutation.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Bone Marrow, Macrophage

SUBMITTER: Simeon Mihaylov

LAB HEAD: Sila Konur Ultanir

PROVIDER: PXD050088 | Pride | 2026-07-09

REPOSITORIES: Pride

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			Action	DRS
	EF2662_Phosphoproteome_all_txt.7z	Other
	EF2662_Total_proteome_all_txt.7z	Other
	EF2662_mihayls_FeNTA.raw	Raw
	EF2662_mihayls_SMOAC_bRP_HCDMS2_F1.raw	Raw
	EF2662_mihayls_SMOAC_bRP_HCDMS2_F2.raw	Raw

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