title: Sialidase NEU4 hydrolyzes polysialic acids of neural cell adhesion molecules and negatively regulates neurite formation by hippocampal neurons.
abstract: Modulation of levels of polysialic acid (polySia), a sialic acid polymer, predominantly associated with the neural cell adhesion molecule (NCAM), influences neural functions, including synaptic plasticity, neurite growth, and cell migration. Biosynthesis of polySia depends on two polysialyltransferases ST8SiaII and ST8SiaIV in vertebrate. However, the enzyme involved in degradation of polySia in its physiological turnover remains uncertain. In the present study, we identified and characterized a murine sialidase NEU4 that catalytically degrades polySia. Murine NEU4, dominantly expressed in the brain, was found to efficiently hydrolyze oligoSia and polySia chains as substrates in sialidase in vitro assays, and also NCAM-Fc chimera as well as endogenous NCAM in tissue homogenates of postnatal mouse brain as assessed by immunoblotting with anti-polySia antibodies. Degradation of polySia by NEU4 was also evident in neuroblastoma Neuro2a cells that were co-transfected with Neu4 and ST8SiaIV genes. Furthermore, in mouse embryonic hippocampal primary neurons, the endogenously expressed NEU4 was found to decrease during the neuronal differentiation. Interestingly, GFP- or FLAG-tagged NEU4 was partially co-localized with polySia in neurites and significantly suppressed their outgrowth, whereas silencing of NEU4 showed the acceleration together with an increase in polySia expression. These results suggest that NEU4 is involved in regulation of neuronal function by polySia degradation in mammals.
authors.affiliation: Division of Cancer Glycosylation Research, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, 981-8558, Japan.
authors.forename: Kohta
authors.initials: K
authors.lastname: Takahashi
authors.forename: Junya
authors.initials: J
authors.lastname: Mitoma
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hosono
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiozaki
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sato
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Kitajima
authors.forename: Hideyoshi
authors.initials: H
authors.lastname: Higashi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nitta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shima
authors.forename: Taeko
authors.initials: T
authors.lastname: Miyagi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism*; D016501:Neurites / Q000378:metabolism*; D012794:Sialic Acids / Q000235:genetics / Q000378:metabolism*; D012799:Sialyltransferases / Q000096:biosynthesis / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D012794:Sialic Acids; C021319:polysialic acid; D012799:Sialyltransferases; C491428:NEU4 protein, human; C481539:Neu4 protein, mouse; D009439:Neuraminidase; C515117:ST8SIA4 protein, human