Journal
JOURNAL OF NEUROSCIENCE
Volume 36, Issue 37, Pages 9633-9646Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.1235-16.2016
Keywords
CMT; O-GlcNAc; OGT; Periaxin; Schwann cell; tomacula
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Funding
- NIH-National Institute of General Medical Sciences (NIGMS) Award [T32GM108539]
- NIH [NS087306, AG13730]
- Muscular Dystrophy Association [237041]
- Hope Center for Neurological Disorders, Washington University
- Biomedical Technology Research Centers program of the NIH-NIGMS
- NIH-NIGMS Grant [8P41GM103481]
- Howard Hughes Medical Institute
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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.
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