TY - JOUR
T1 - Parkinson’s associated protein DJ-1 regulates intercellular communication via extracellular vesicles in oxidative stress
AU - Page, Thomas
AU - Musi, Clara Alice
AU - Bakker, Saskia E.
AU - Jenkins, David R.
AU - Hill, Eric J.
AU - Borsello, Tiziana
AU - Milic, Ivana
AU - Devitt, Andrew
AU - Repici, Mariaelena
N1 - Copyright © The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/
PY - 2025/11/21
Y1 - 2025/11/21
N2 - Mutations in DJ-1 cause autosomal recessive Parkinson’s disease (PD). 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’s disease pathogenesis.
AB - Mutations in DJ-1 cause autosomal recessive Parkinson’s disease (PD). 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’s disease pathogenesis.
UR - https://www.nature.com/articles/s41420-025-02845-7
UR - http://www.scopus.com/inward/record.url?scp=105022626331&partnerID=8YFLogxK
U2 - 10.1038/s41420-025-02845-7
DO - 10.1038/s41420-025-02845-7
M3 - Article
SN - 2058-7716
VL - 11
JO - Cell Death Discovery
JF - Cell Death Discovery
M1 - 539
ER -