title: Reduced protein O-glycosylation in the nervous system of the mutant SOD1 transgenic mouse model of amyotrophic lateral sclerosis.
abstract: In the neurodegenerative disease amyotrophic lateral sclerosis (ALS), a number of proteins have been found to be hyperphosphorylated, including neurofilament proteins (NFs). In addition to protein phosphorylation, another important post-translational modification is O-glycosylation with β-N-acetylglucosamine residues (O-GlcNAc) and it has been found that O-GlcNAc can modify proteins competitively with protein phosphorylation, so that increased O-GlcNAc can reduce phosphorylation at specific sites. We evaluated a transgenic mouse model of ALS that overexpresses mutant superoxide dismutase (mSOD) and found that O-GlcNAc immunoreactivity levels are decreased in spinal cord tissue from mSOD mice, compared to controls. This reduction in O-GlcNAc levels is prominent in the motor neurons of spinal cord. We find that inhibition of O-GlcNAcase (OGA), the enzyme catalyzing removal of O-GlcNAc, using the inhibitor NButGT for 3 days, resulted in increased O-GlcNAc levels in spinal cord, both in mSOD and control mice. Furthermore, NButGT increased levels of O-GlcNAc modified NF-medium in spinal cords of control mice, but not in mSOD mice. These observations suggest that the neurodegeneration found in mSOD mice is associated with a reduction of O-GlcNAc levels in neurons, including motor neurons.
authors.affiliation: Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Shan
authors.forename: David J
authors.initials: DJ
authors.lastname: Vocadlo
authors.forename: Charles
authors.initials: C
authors.lastname: Krieger
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D006031:Glycosylation; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D011506:Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1