O-GlcNAc regulation of autophagy and α-synuclein homeostasis; implications for Parkinson's disease

• Published in: Molecular brain Vol. 10; no. 1; pp. 32 - 14
• Main Authors: Wani, Willayat Y, Ouyang, Xiaosen, Benavides, Gloria A, Redmann, Matthew, Cofield, Stacey S, Shacka, John J, Chatham, John C, Darley-Usmar, Victor, Zhang, Jianhua
• Format: Journal Article
• Language: English
• Published: England BioMed Central 19.07.2017; BMC
• Subjects: AKT protein; alpha-Synuclein - metabolism; Animals; Apoptosis; Autophagy; Autophagy - drug effects; Bioenergetics; Brain; Cells, Cultured; Disease; Glucosamine; Glucosamine - metabolism; Glycosylation - drug effects; Homeostasis; Humans; Kinases; Lysates; Mitochondria; Models, Biological; N-Acetylglucosamine; Neurodegeneration; Neurodegenerative diseases; Neurons - drug effects; Neurons - metabolism; O-GlcNAcylation; Oxidative stress; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathogenesis; Phagocytosis; Phosphorylation; Phosphorylation - drug effects; Post-translation; Postmortem Changes; Proteasome; Proteasomes; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyrans - pharmacology; Rapamycin; Rats, Sprague-Dawley; Regulation; Signal Transduction - drug effects; Sirolimus - pharmacology; Synuclein; Temporal lobe; Thiazoles - pharmacology; TOR protein; TOR Serine-Threonine Kinases - metabolism; α-synuclein; Mitochondria; Thiamet G; mTOR; O-GlcNAcylation; Rapamycin; Akt; Autophagy; Parkinson’s disease; α-synuclein; Proteasome
• ISSN: 1756-6606; 1756-6606
• DOI: 10.1186/s13041-017-0311-1

Post-translational modification on protein Ser/Thr residues by O-linked attachment of ß-N-acetyl-glucosamine (O-GlcNAcylation) is a key mechanism integrating redox signaling, metabolism and stress responses. One of the most common neurodegenerative diseases that exhibit aberrant redox signaling, metabolism and stress response is Parkinson's disease, suggesting a potential role for O-GlcNAcylation in its pathology. To determine whether abnormal O-GlcNAcylation occurs in Parkinson's disease, we analyzed lysates from the postmortem temporal cortex of Parkinson's disease patients and compared them to age matched controls and found increased protein O-GlcNAcylation levels. To determine whether increased O-GlcNAcylation affects neuronal function and survival, we exposed rat primary cortical neurons to thiamet G, a highly selective inhibitor of the enzyme which removes the O-GlcNAc modification from target proteins, O-GlcNAcase (OGA). We found that inhibition of OGA by thiamet G at nanomolar concentrations significantly increased protein O-GlcNAcylation, activated MTOR, decreased autophagic flux, and increased α-synuclein accumulation, while sparing proteasomal activities. Inhibition of MTOR by rapamycin decreased basal levels of protein O-GlcNAcylation, decreased AKT activation and partially reversed the effect of thiamet G on α-synuclein monomer accumulation. Taken together we have provided evidence that excessive O-GlcNAcylation is detrimental to neurons by inhibition of autophagy and by increasing α-synuclein accumulation.