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Several functions have been attributed to DJ-1, including a key role in the protection from oxidative stress. However, how this protein contributes to PD pathogenesis is still unclear. Recently, DJ-1 has been identified at higher concentrations in extracellular vesicles (EV) from biological fluids of PD patients, providing a link between EV and a protein associated with PD. In this study, EV were purified from the medium of control and rotenone-treated wild-type and DJ-1 KO differentiated SH-SY5Y cells. EV quantity was assessed using flow cytometry, and their proteomic cargo was analysed via mass spectrometry. We identified an altered EV response to rotenone in DJ-1 KO cells compared to wild-type. Mass spectrometry analysis identified 116 proteins with significantly altered abundance between the two genotypes, indicating a role for DJ-1 in modulating EV cargo under oxidative stress conditions. Label-free identification of oxidative modifications indicated that DJ-1 clearly influences the oxidative profile of EV proteins. Additionally, we showed that DJ-1 KO alters the ability of the secretome to stimulate macrophage migration, suggesting functional consequences of DJ-1 deficiency in secretome-mediated responses to oxidative stress. The altered EV response to rotenone was confirmed in iPSC-derived neurons lacking DJ-1 compared to isogenic controls. Our results reveal a distinct role for DJ-1 in regulating intercellular communication under oxidative stress, highlighting a novel EV-mediated function of DJ-1 that may contribute to Parkinson\u2019s disease pathogenesis.<\/jats:p>","DOI":"10.1038\/s41420-025-02845-7","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T14:24:35Z","timestamp":1763735075000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Parkinson\u2019s associated protein DJ-1 regulates intercellular communication via extracellular vesicles in oxidative stress"],"prefix":"10.1038","volume":"11","author":[{"given":"Thomas","family":"Page","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara Alice","family":"Musi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3958-4421","authenticated-orcid":false,"given":"Saskia E.","family":"Bakker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Jenkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric J.","family":"Hill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Borsello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7531-7561","authenticated-orcid":false,"given":"Ivana","family":"Milic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4651-6761","authenticated-orcid":false,"given":"Andrew","family":"Devitt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9420-528X","authenticated-orcid":false,"given":"Mariaelena","family":"Repici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"2845_CR1","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1126\/science.1077209","volume":"299","author":"V Bonifati","year":"2003","unstructured":"Bonifati V, Rizzu P, van Baren MJ, Schaap O, Breedveld GJ, Krieger E, et al. 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