The deposition of α‐synuclein inclusions known as Lewy bodies and the loss of dopaminergic neurons are hallmark pathological changes contributing to the motor and nonmotor symptoms of Parkinson's disease. The concomitant neuroinflammation, characterized by activated microglia and astroglia and the secretion of pro‐inflammatory cytokines, is known to trigger neurodegenerative processes in PD. Necroptosis is a mechanism of cell death that can be less inflammatory than pyroptosis by initiating cell death before the release of pro‐inflammatory cytokines. The innate immune sensor, Z‐DNA binding protein 1 (ZBP1), plays a role in necroptosis by activating downstream kinases leading to the formation of a cationic pore in the membrane. Recently, we have shown that α‐synuclein can act as the primer and trigger for pyroptosis. In the present study, we characterized ZBP1's role in the aggregated α‐synuclein‐induced neuroinflammatory response using the mouse microglial cell line (MMC), primary mouse microglia (PMG), and the human astrocytoma, U373 cells. After treating MMCs, PMGs, and U373s with aggregated α‐synuclein, we observed a decease in ZBP1 using Western blot analysis and this decrease was observed at 24 hours but not at earlier time points. We then used small interfering RNA (siRNA) to knock down ZBP1 in MMCs and used Luminex multiplex cytokine assay to measure the levels of secreted pro‐inflammatory cytokines in the media. This analysis revealed an increase in interleukin (IL)‐1β, IL‐6, IL‐17A, tumor necrosis factor α (TNF‐α), and interferon‐γ (IFN‐γ) in the media. Our data suggest that loss of ZBP1 in glial cells skews them towards more potent pro‐inflammatory signaling pathways known to be activated by aggregated alpha‐synuclein. Studies are underway to characterize the regulatory role of ZBP1 in α‐synuclein‐induced necroptosis and pyroptosis in glia cells during α‐synuclein neurotoxicity. Support or Funding Information (NIH grants NS100090, NS088206, ES026892) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .