title: Schwann Cell O-GlcNAc Glycosylation Is Required for Myelin Maintenance and Axon Integrity.
abstract: Schwann cells (SCs), ensheathing glia of the peripheral nervous system, support axonal survival and function. Abnormalities in SC metabolism affect their ability to provide this support and maintain axon integrity. To further interrogate this metabolic influence on axon-glial interactions, we generated OGT-SCKO mice with SC-specific deletion of the metabolic/nutrient sensing protein O-GlcNAc transferase that mediates the O-linked addition of N-acetylglucosamine (GlcNAc) moieties to Ser and Thr residues. The OGT-SCKO mice develop tomaculous demyelinating neuropathy characterized by focal thickenings of the myelin sheath (tomacula), progressive demyelination, axonal loss, and motor and sensory nerve dysfunction. Proteomic analysis identified more than 100 O-GlcNAcylated proteins in rat sciatic nerve, including Periaxin (PRX), a myelin protein whose mutation causes inherited neuropathy in humans. PRX lacking O-GlcNAcylation is mislocalized within the myelin sheath of these mutant animals. Furthermore, phenotypes of OGT-SCKO and Prx-deficient mice are very similar, suggesting that metabolic control of PRX O-GlcNAcylation is crucial for myelin maintenance and axonal integrity.
  
  
  
  The nutrient sensing protein O-GlcNAc transferase (OGT) mediates post-translational O-linked N-acetylglucosamine (GlcNAc) modification. Here we find that OGT functions in Schwann cells (SCs) to maintain normal myelin and prevent axonal loss. SC-specific deletion of OGT (OGT-SCKO mice) causes a tomaculous demyelinating neuropathy accompanied with progressive axon degeneration and motor and sensory nerve dysfunction. We also found Periaxin (PRX), a myelin protein whose mutation causes inherited neuropathy in humans, is O-GlcNAcylated. Importantly, phenotypes of OGT-SCKO and Prx mutant mice are very similar, implying that compromised PRX function contributes to the neuropathy of OGT-SCKO mice. This study will be useful in understanding how SC metabolism contributes to PNS function and in developing new strategies for treating peripheral neuropathy by targeting SC function.
authors.affiliation: Department of Genetics and.
authors.forename: Sungsu
authors.identifier: 0000-0002-8644-2517
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158-2517, and.
authors.forename: Jason C
authors.identifier: 0000-0001-7838-5420
authors.initials: JC
authors.lastname: Maynard
authors.affiliation: Department of Genetics and.
authors.forename: Yo
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Genetics and.
authors.forename: Amy
authors.initials: A
authors.lastname: Strickland
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Sherman
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom.
authors.forename: Peter J
authors.identifier: 0000-0002-0262-9545
authors.initials: PJ
authors.lastname: Brophy
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158-2517, and.
authors.forename: Alma L
authors.initials: AL
authors.lastname: Burlingame
authors.affiliation: Department of Genetics and Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, Missouri 63110, jmilbrandt@wustl.edu.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000200:Action Potentials / Q000235:genetics; D000818:Animals; D020274:Autoimmune Diseases of the Nervous System / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009431:Neural Conduction / Q000235:genetics; D040901:Proteomics; D012584:Sciatic Nerve / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D014404:Tubulin / Q000378:metabolism
chemical_list: C499047:Mbp protein, mouse; D008565:Membrane Proteins; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D014404:Tubulin; C086745:periaxin; D017351:N-Acetylglucosaminyltransferases; C449880:O-GlcNAc transferase; D005947:Glucose; D000117:Acetylglucosamine
keywords: CMT; O-GlcNAc; OGT; Periaxin; Schwann cell; tomacula