Fig. 8
From: O-GlcNAc regulation of autophagy and α-synuclein homeostasis; implications for Parkinson’s disease
Working model. In our study we demonstrated that Parkinson’s disease postmortem brains exhibit increased O-GlcNAcylated proteins. Increasing O-GlcNAcylated proteins by inhibition of OGA, the enzyme responsible for O-GlcNAc removal, resulted in MTOR activation, AKT phosphorylation, and attenuation of autophagic flux. Prolonged inhibition of OGA increased α-synuclein accumulation and resulted in cell death. Prior studies suggest that an increase in AKT phosphorylation may attenuate autophagy by phosphorylating BECN and attenuate chaperone mediated autophagy by modulating translocation complex stability. Rapamycin inhibits MTOR activation and can partially reverse thiamet G effects on p62 and α-synuclein accumulation