title: Ablation of keratan sulfate accelerates early phase pathogenesis of ALS.
abstract: Biopolymers consist of three major classes, i.e., polynucleotides (DNA, RNA), polypeptides (proteins) and polysaccharides (sugar chains). It is widely accepted that polynucleotides and polypeptides play fundamental roles in the pathogenesis of neurodegenerative diseases. But, sugar chains have been poorly studied in this process, and their biological/clinical significance remains largely unexplored. Amyotrophic lateral sclerosis (ALS) is a motoneuron-degenerative disease, the pathogenesis of which requires both cell autonomous and non-cell autonomous processes. Here, we investigated the role of keratan sulfate (KS), a sulfated long sugar chain of proteoglycan, in ALS pathogenesis. We employed ALS model SOD1(G93A) mice and GlcNAc6ST-1(-/-) mice, which are KS-deficient in the central nervous system. Unexpectedly, SOD1(G93A)GlcNAc6ST-1(-/-) mice exhibited a significantly shorter lifespan than SOD1(G93A) mice and an accelerated appearance of clinical symptoms (body weight loss and decreased rotarod performance). KS expression was induced exclusively in a subpopulation of microglia in SOD1(G93A) mice, and became detectable around motoneurons in the ventral horn during the early disease phase before body weight loss. During this phase, the expression of M2 microglia markers was transiently enhanced in SOD1(G93A) mice, while this enhancement was attenuated in SOD1(G93A)GlcNAc6ST-1(-/-) mice. Consistent with this, M2 microglia were markedly less during the early disease phase in SOD1(G93A)GlcNAc6ST-1(-/-) mice. Moreover, KS expression in microglia was also detected in some human ALS cases. This study suggests that KS plays an indispensable, suppressive role in the early phase pathogenesis of ALS and may represent a new target for therapeutic intervention.
authors.affiliation: Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Hirano
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ohgomori
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Natori
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Matsuyama
authors.forename: Kenji
authors.initials: K
authors.lastname: Uchimura
authors.forename: Kazuma
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hirakawa
authors.forename: Akio
authors.initials: A
authors.lastname: Suzumura
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.forename: Shiro
authors.initials: S
authors.lastname: Imagama
authors.forename: Kenji
authors.initials: K
authors.lastname: Kadomatsu
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051940:B7-2 Antigen / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007632:Keratan Sulfate / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism; D009154:Mutation; D013116:Spinal Cord / Q000378:metabolism; D015238:Sulfotransferases / Q000172:deficiency; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013997:Time Factors; D000097811:Carbohydrate Sulfotransferases
chemical_list: D051940:B7-2 Antigen; D015415:Biomarkers; D007632:Keratan Sulfate; D015238:Sulfotransferases; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000097811:Carbohydrate Sulfotransferases; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse