Protective effect of increased O-GlcNAc cycling against 6-OHDA induced Parkinson's disease pathology

This study aimed to elucidate the role of O-GlcNAc cycling in 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD)-like neurodegeneration and the underlying mechanisms. We observed dose-dependent downregulation of O-GlcNAcylation, accompanied by an increase in O-GlcNAcase following 6-OHDA treatment in both mouse brain and Neuro2a cells. Intriguingly, elevation of O-GlcNAcylation through glucosamine (GlcN) injection provided protection against PD pathogenesis induced by 6-OHDA. At the behavioral level, GlcN ameliorated motor deficits induced by 6-OHDA, as determined using the pole, cylinder, and apomorphine rotation tests. Additionally, GlcN alleviated 6-OHDA-induced neuroinflammation and mitochondrial dysfunction. Remarkably, elevated O-GlcNAcylation, achieved through O-GlcNAc transferase (OGT) overexpression in mouse brain, provided protection against 6-OHDA-induced PD pathology encompassing neuronal cell death, motor deficits, neuroinflammation, and mitochondrial dysfunction. Our collective findings imply that O-GlcNAcylation plays a crucial role in the normal functioning of dopamine neurons. Furthermore, enhancement of O-GlcNAcylation through genetic and pharmacological manipulation could effectively alleviate neurodegeneration and motor impairment in an animal model of PD. These results offer a potential strategy for protecting against deterioration of dopamine neurons implicated in PD pathogenesis.