The critical role of O-GlcNAcylation in dopamine neuron function, survival, and degeneration in health and Parkinson’s disease

Abstract

Dopamine system in the midbrain is important for volitional movement, action selection, and reward-related learning. Even though dopamine system mediates versatile functions, it contains only a small set of neurons in the midbrain. Moreover, these dopamine neurons are highly susceptible to Parkinson’s disease (PD) and degenerate during disease progression. Here, we reveal that O-GlcNAcylation, an important post-translational modification in cells, is essential for survival and function of dopamine neurons. Modulation of O-GlcNAc level critically regulates dopamine neurons at molecular, synaptic, cellular, and behavioral levels. Notably, up-regulation of O-GlcNAcylation in dopamine neurons alleviates neurodegeneration, synaptic impairments, and motor deficits in an animal model of PD. These findings suggest the importance of O-GlcNAcylation in the dopamine system and may provide new therapeutic approach to protect dopamine neurons against PD pathology.