title: Microglial keratan sulfate epitope elicits in central nervous tissues of transgenic model mice and patients with amyotrophic lateral sclerosis.
abstract: The functional role of 5D4 antibody-reactive keratan sulfate (KS) in the pathogenesis of neurodegenerative diseases is unknown. We therefore studied the expression of 5D4-reactive KS in amyotrophic lateral sclerosis (ALS), a motor neuron-degenerative disease, with the use of SOD1(G93A) ALS model mice and patients with ALS. Histochemical and immunoelectron microscopic characterizations showed that the 5D4-reactive KS is expressed in Mac2/galectin-3-positive activated or proliferating microglia of SOD1(G93A) ALS model mice at disease end stage and that the KS is an O-linked glycan modified with sialic acid and fucose, which was thus far shown to exist in cartilage. Intriguingly, microglial KS was detected in the spinal cord and brainstem but not in the cerebral cortex of SOD1(G93A) mice. We found that KSGal6ST, a galactose-6-sulfotransferase, is required for biosynthesis of the microglial 5D4-reactive KS by generating SOD1(G93A)/KSGal6ST(-/-) mice. The requirement of GlcNAc6ST1 for this synthesis was corroborated by analyzing SOD1(G93A)/GlcNAc6ST1(-/-) mice. These results indicate that both galactose-6- and N acteylglucosamine-6-sulfated KS elicited in the spinal cord and brainstem are associated with the degeneration of spinal and bulbar lower motor neurons in ALS pathology and may play a role in disease progression via microglial activation and proliferation.
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tahmina
authors.initials: T
authors.lastname: Foyez
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Takeda-Uchimura
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ishigaki
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.lastname: Narentuya
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Zui
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: kkadoma@med.nagoya-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: arumihcu@med.nagoya-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Uchimura
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000276:immunology* / Q000401:mortality / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D005260:Female; D037502:Galectin 3 / Q000378:metabolism; D006801:Humans; D007632:Keratan Sulfate / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism; D020125:Mutation, Missense; D013116:Spinal Cord / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000276:immunology; D000097811:Carbohydrate Sulfotransferases
chemical_list: D000939:Epitopes; D037502:Galectin 3; D007632:Keratan Sulfate; D015238:Sulfotransferases; D013482:Superoxide Dismutase; D000097811:Carbohydrate Sulfotransferases; C485095:Lgals3 protein, mouse