title: Heparan sulfate saccharides modify focal adhesions: implication in mucopolysaccharidosis neuropathophysiology.
abstract: Mucopolysaccharidoses type III (MPSIII, Sanfilippo syndrome) are genetic diseases due to deficient heparan sulfate (HS) saccharide digestion by lysosomal exoglycanases. Progressive accumulation of undigested saccharides causes early-onset behavioural and cognitive symptoms. The precise role of these saccharides in the pathophysiological cascade is still unclear. We showed that exposure of wild-type neural cells to exogenous soluble HS fragments of at least eight saccharides activated integrin-based focal adhesions (FAs), which attach cells to the extracellular matrix. FAs were constitutively activated in MPSIII type B astrocytes or neural stem cells unless undigested saccharides were cleared by exogenous supply of the missing exoglycanase. Defective cell polarisation and oriented migration in response to focal extracellular stimuli in affected cells suggest improper sensing of the environment. We consistently observed abnormal organisation of the rostral migratory stream in the brain of adult mice with MPSIII type B. These results suggest that cell polarisation and oriented migration defects participate to the neurological disorders associated with Sanfilippo syndrome.
authors.affiliation: Biotherapy and Neurodegenerative Diseases Unit, INSERM U1115, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Bruyère
authors.affiliation: Biotherapy and Neurodegenerative Diseases Unit, INSERM U1115, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Roy
authors.affiliation: Laboratoire de Biochimie, CHU Amiens, UFR de Médecine, INSERM U1088, Avenue Laënnec, 80054 Amiens, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Ausseil
authors.affiliation: Biotherapy and Neurodegenerative Diseases Unit, INSERM U1115, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemonnier
authors.affiliation: Biotherapy and Neurodegenerative Diseases Unit, INSERM U1115, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Teyre
authors.affiliation: Biotherapy and Neurodegenerative Diseases Unit, INSERM U1115, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Bohl
authors.affiliation: Cell Polarity and Migration Group and CNRS URA 2582, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Etienne-Manneville
authors.affiliation: CNRS-Commissariat à l'Energie Atomique-Université Joseph Fourier, Grenoble 1, Institut de Biologie Structurale Jean-Pierre Ebel, 6 rue Jules Horowitz, 38027 Grenoble Cedex 01, France.
authors.forename: Hugues
authors.initials: H
authors.lastname: Lortat-Jacob
authors.affiliation: Biotherapy and Neurodegenerative Diseases Unit, INSERM U1115, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France. Electronic address: jmheard@pasteur.fr.
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Heard
authors.affiliation: Biotherapy and Neurodegenerative Diseases Unit, INSERM U1115, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris Cedex 15, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vitry
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D016764:Cell Polarity / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009084:Mucopolysaccharidosis III / Q000473:pathology*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D051419:Paxillin / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D013552:Swine
chemical_list: D051417:Focal Adhesion Kinase 1; D006497:Heparan Sulfate; D051419:Paxillin; C496062:Pxn protein, mouse; C496050:PTK2 protein, human
keywords: cell polarisation; focal adhesion; glycosaminoglycans; mucopolysaccharidosis; neural cell migration