Extracellular vesicle-mediated release of bis(monoacylglycerol)phosphate is regulated by LRRK2 and Glucocerebrosidase activity

• DOI: 10.7554/elife.106330.1
• Publication Date: 2025-05-23T14:30:45Z
• Authors: Elsa Meneses-Salas; Marianna Arnold; Moises Castellá; Frank Hsieh; Ruben Fernández-S...; Mario Ezquerra; Alicia Garrido; María-José Martí; Carlos Enric; Suzanne R Pfeffer; Kalpana Merchant; Albert Lu
• Keywords: Extracellular Vesicles; LRRK2

Abstract The endo-lysosomal phospholipid, bis(monoacylglycerol)phosphate (BMP), is aberrantly elevated in the urine of Parkinson’s patients with mutations genes encoding leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GCase). Because BMP resides on regulates biogenesis intralumenal membranes that become extracellular vesicles (EVs) upon release, we hypothesized urinary may be driven by increased exocytosis BMP-enriched EVs. To test this hypothesis, analyzed metabolism EV-associated release wild type (WT) R1441G LRRK2-expressing mouse embryonic fibroblast (MEF) cells. Using immunofluorescence microscopy transmission electron detected structural alterations endo-lysosomes antibody-accessible pool, indicating mutant LRRK2 affects endolysosomal homeostasis. Biochemical analyses isolated EV fractions confirmed effect showing an increase LAMP2-positive EVs cells, which was partially restored inhibition but further augmented GCase inhibition. mass spectrometry, overall total di-22:6-BMP di-18:1-BMP cell lysates from MEFs compared to WT Inhibition cellular levels, whereas content. In decreased content tended it. metabolic labeling experiments, demonstrated not due synthesis, even though observed synthesizing enzyme, CLN5, patient-derived fibroblasts. Finally, pharmacological modulators associated secretion. Together, these results establish as a regulator levels cells its through EVs, activity modulating process Mechanistic insights studies have implications for potential use BMP-positive biomarker disease treatments.