title: Loss of O-GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration.
abstract: O-GlcNAc glycosylation (or O-GlcNAcylation) is a dynamic, inducible posttranslational modification found on proteins associated with neurodegenerative diseases such as α-synuclein, amyloid precursor protein, and tau. Deletion of the O-GlcNAc transferase (ogt) gene responsible for the modification causes early postnatal lethality in mice, complicating efforts to study O-GlcNAcylation in mature neurons and to understand its roles in disease. Here, we report that forebrain-specific loss of OGT in adult mice leads to progressive neurodegeneration, including widespread neuronal cell death, neuroinflammation, increased production of hyperphosphorylated tau and amyloidogenic Aβ-peptides, and memory deficits. Furthermore, we show that human cortical brain tissue from Alzheimer's disease patients has significantly reduced levels of OGT protein expression compared with cortical tissue from control individuals. Together, these studies indicate that O-GlcNAcylation regulates pathways critical for the maintenance of neuronal health and suggest that dysfunctional O-GlcNAc signaling may be an important contributor to neurodegenerative diseases.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Wang
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Jensen
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Rexach
authors.affiliation: Division of Neuropathology, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095.|Department of Neurology, David Geffen School of Medicine at University of California, Los Angeles, CA 90095.
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125; lhw@caltech.edu.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Hsieh-Wilson
mesh_terms: D000117:Acetylglucosamine / Q000737:chemistry*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001931:Brain Mapping; D003433:Crosses, Genetic; D005260:Female; D006031:Glycosylation; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D008297:Male; D008569:Memory Disorders; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000737:chemistry*; D019636:Neurodegenerative Diseases / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000737:chemistry* / Q000473:pathology; D010766:Phosphorylation; D016548:Prosencephalon / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D000117:Acetylglucosamine
keywords: O-GlcNAc; amyloid beta; glycosylation; neurodegeneration; tau