O‐GlcNAcylation Mediated by OGA Activates NEK7/NLRP3 Pathway to Promote Pyroptosis in Parkinson's Disease

Parkinson's disease (PD) is a neurodegenerative disorder characterised by pyroptosis. O‐GlcNAcylation, regulated solely by O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA), has been shown to mitigate PD. This study aimed to investigate whether pyroptosis and PD pathogenesis are modulated by O‐GlcNAcylation. In PD model cells, O‐GlcNAc protein levels were downregulated, while OGA expression was upregulated. Knockdown of OGA significantly protected BV2 cells from LPS‐induced injury by inhibiting pyroptosis. Inhibition of OGA notably increased the O‐GlcNAc levels of NEK7. Furthermore, O‐GlcNAcylated NEK7 protein levels were significantly reduced by mutations at T170 or T172, whereas phosphorylated NEK7 protein levels were downregulated only by mutations at T172. Co‐immunoprecipitation (co‐IP) confirmed the endogenous interaction between NEK7 and NLRP3, which was weakened by OGA knockdown. In animal experiments, OGA deficiency significantly reduced motor dysfunctions and dopaminergic neurodegeneration in MPTP‐treated mice. OGT deficiency abolished the protective effects of OGA knockdown against MPTP‐induced injury. Additionally, OGT inhibition in OGA knockdown mice promoted pyroptosis. Collectively, these findings indicate that high OGA levels decrease O‐GlcNAcylation in PD, thereby promoting pyroptosis via the activation of the NEK7/NLRP3 pathway.