DJ‐1 deficiency in astrocytes selectively enhances mitochondrial Complex I inhibitor‐induced neurotoxicity

J. Neurochem. (2011) 117 , 375–387. Abstract Parkinson’s disease (PD) brains show evidence of mitochondrial respiratory Complex I deficiency, oxidative stress, and neuronal death. Complex I‐inhibiting neurotoxins, such as the pesticide rotenone, cause neuronal death and parkinsonism in animal models. We have previously shown that DJ‐1 over‐expression in astrocytes augments their capacity to protect neurons against rotenone, that DJ‐1 knock‐down impairs astrocyte‐mediated neuroprotection against rotenone, and that each process involves astrocyte‐released factors. To further investigate the mechanism behind these findings, we developed a high‐throughput, plate‐based bioassay that can be used to assess how genetic manipulations in astrocytes affect their ability to protect co‐cultured neurons. We used this bioassay to show that DJ‐1 deficiency‐induced impairments in astrocyte‐mediated neuroprotection occur solely in the presence of pesticides that inhibit Complex I (rotenone, pyridaben, fenazaquin, and fenpyroximate); not with agents that inhibit Complexes II–V, that primarily induce oxidative stress, or that inhibit the proteasome. This is a potentially PD‐relevant finding because pesticide exposure is epidemiologically‐linked with an increased risk for PD. Further investigations into our model suggested that astrocytic GSH and heme oxygenase‐1 antioxidant systems are not central to the neuroprotective mechanism.