title: Differential distribution of heparan sulfate glycoforms and elevated expression of heparan sulfate biosynthetic enzyme genes in the brain of mucopolysaccharidosis IIIB mice.
abstract: The primary pathology in mucopolysaccharidosis (MPS) IIIB is lysosomal storage of heparan sulfate (HS) glycosaminoglycans, leading to complex neuropathology and dysfunction, for which the detailed mechanisms remain unclear. Using antibodies that recognize specific HS glycoforms, we demonstrate differential cell-specific and domain-specific lysosomal HS-GAG distribution in MPS IIIB mouse brain. We also describe a novel neuron-specific brain HS epitope with broad, non-specific increase in the expression in all neurons in MPS IIIB mouse brain, including cerebellar granule neurons, which do not exhibit lysosomal storage pathology. This suggests that biosynthesis of certain HS glycoforms is enhanced throughout the CNS of MPS IIIB mice. Such a conclusion is further supported by demonstration of increased expression of multiple genes encoding enzymes essential in HS biosynthesis, including HS sulfotransferases and epimerases, as well as FGFs, for which HS serves as a co-receptor, in MPS IIIB brain. These data suggest that lysosomal storage of HS may lead to the increase in HS biosyntheses, which may contribute to the neuropathology of MPS IIIB by exacerbating the lysosomal HS storage.
authors.affiliation: The Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, The Ohio State University, 700 Children's Drive, Columbus, OH 43205, USA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: McCarty
authors.forename: Julianne
authors.initials: J
authors.lastname: DiRosario
authors.forename: Kadra
authors.initials: K
authors.lastname: Gulaid
authors.forename: Smruti
authors.initials: S
authors.lastname: Killedar
authors.forename: Arie
authors.initials: A
authors.lastname: Oosterhof
authors.forename: Toin H
authors.initials: TH
authors.lastname: van Kuppevelt
authors.forename: Paul T
authors.initials: PT
authors.lastname: Martin
authors.forename: Haiyan
authors.initials: H
authors.lastname: Fu
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002238:Carbohydrate Epimerases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D006497:Heparan Sulfate / Q000096:biosynthesis*; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009084:Mucopolysaccharidosis III / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D020033:Protein Isoforms / Q000032:analysis; D015238:Sulfotransferases / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D002238:Carbohydrate Epimerases; D005346:Fibroblast Growth Factors; D006497:Heparan Sulfate; D020033:Protein Isoforms; D015238:Sulfotransferases