title: Enhanced degradation of synaptophysin by the proteasome in mucopolysaccharidosis type IIIB.
abstract: The interruption of the lysosomal degradation of heparan sulfate oligosaccharides has deleterious consequences on the central nervous system in children or in animals with mucopolysaccharidosis type III (Sanfilippo syndrome). Behavioural manifestations are prominent at disease onset, suggesting possible early synaptic defects in cortical neurons. We report that synaptophysin, the most abundant protein of the synaptic vesicle membrane, was detected at low levels in the rostral cortex of MPSIII type B mice as early as 10 days after birth. This defect preceded other disease manifestations, was associated with normal neuron and synapse density and corrected after gene transfer inducing re-expression of the missing lysosomal enzyme. Clearance of heparan sulfate oligosaccharides in cultured embryonic MPSIIIB cortical neurons or treatment with proteasome inhibitors restored normal synaptophysin levels indicating that heparan sulfate oligosaccharides activate the degradation of synaptophysin by the proteasome with consequences on synaptic vesicle components that are relevant to clinical manifestations.
authors.affiliation: Unité Rétrovirus et Transfert Génétique, INSERM U622, Department of Neuroscience, Institut Pasteur, 28 rue du Dr Roux, 75724 Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Vitry
authors.forename: Jérôme
authors.initials: J
authors.lastname: Ausseil
authors.forename: Michael
authors.initials: M
authors.lastname: Hocquemiller
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bigou
authors.forename: Renata
authors.initials: R
authors.lastname: Dos Santos Coura
authors.forename: Jean Michel
authors.initials: JM
authors.lastname: Heard
mesh_terms: D000118:Acetylglucosaminidase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001519:Behavior / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002648:Child; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009084:Mucopolysaccharidosis III / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D050683:R-SNARE Proteins / Q000378:metabolism; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism*
chemical_list: D000118:Acetylglucosaminidase; D019922:GAP-43 Protein; D006497:Heparan Sulfate; D046988:Proteasome Endopeptidase Complex; D050683:R-SNARE Proteins; D016708:Synaptophysin