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We analyzed BMP metabolism and EV-associated BMP release in wild-type (WT) and R1441G LRRK2 mouse embryonic fibroblasts (MEFs). Immunofluorescence and transmission electron microscopy revealed structural alterations in endolysosomes and the antibody-accessible BMP pool, indicating disrupted endolysosomal homeostasis. Biochemical analysis of isolated EV fractions showed increased release of LAMP2-positive EVs by mutant cells, partially restored by LRRK2 kinase inhibition but further, variably, increased by GCase inhibition. Mass spectrometry detected higher total di-22:6-BMP and di-18:1-BMP in mutant LRRK2 MEFs compared to WT. Inhibition of LRRK2 partially restored cellular BMP, whereas GCase inhibition further elevated it. In EVs from mutant cells, LRRK2 inhibition reduced BMP content, while GCase inhibition tended to increase it. Metabolic labeling showed elevated BMP was not due to increased synthesis, despite higher levels of the BMP-synthesizing enzyme CLN5 in mutant MEFs and patient fibroblasts. Finally, pharmacological modulation of EV release and live total internal reflection fluorescence imaging in human G2019S LRRK2 fibroblasts further confirmed that BMP release is likely associated with EV secretion. Together, these results establish LRRK2 as a regulator of BMP in cells and its release through EVs and suggest that GCase activity further modulates this process in LRRK2 mutant cells. Mechanistic insights from these studies have implications for the use of BMP-positive EVs as potential biomarkers for Parkinson\u2019s disease.<\/jats:p>","DOI":"10.7554\/elife.106330","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T10:30:27Z","timestamp":1747996227000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.106330","source":"Crossref","is-referenced-by-count":3,"title":["Extracellular vesicle-mediated release of bis(monoacylglycerol)phosphate is regulated by LRRK2 and glucocerebrosidase activity"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7550-253X","authenticated-orcid":true,"given":"Elsa","family":"Meneses-Salas","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/021018s57","id-type":"ROR","asserted-by":"publisher"}],"name":"Departament de Biomedicina, Unitat de Biologia Cel\u00b7lular, Facultat de Medicina i Ci\u00e8ncies de la Salut, Centre de Recerca Biom\u00e8dica CELLEX, 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