Parkinson’s associated protein DJ-1 regulates intercellular communication via extracellular vesicles in oxidative stress.

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Abstract Mutations in DJ-1 cause autosomal recessive Parkinson’s disease. 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 concentration in extracellular vesicles (EV) from biological fluids of PD patients, providing a link between EV and a protein associated with PD. EV were isolated from the medium of control and rotenone-treated wild-type and DJ-1 KO differentiated SH-SY5Y cells, their number was evaluated by flow cytometry and the proteomic signature of their cargo was investigated by mass spectrometry analysis. Migration of THP-1 derived macrophages was used a read out for functional EV. The results obtained were validated in iPSC-derived neuronal cells. 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 different concentrations between the two genotypes, suggesting a link between DJ-1 and EV cargo in response to oxidative stress. Additionally, we showed that DJ-1 KO alters the ability of EV to stimulate macrophage migration, thus implying functional consequences for DJ-1 absence in the EV mediated response to oxidative stress. The altered EV response to rotenone was confirmed in iPSC-derived neurons lacking DJ-1 compared to isogenic controls. Our results indicate a clear DJ-1 role in intercellular communication in oxidative stress, underlying a new EV mediated DJ-1 function that may be relevant to PD pathogenesis.

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