title: Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model.
abstract: Severe progressive neurological paediatric disease mucopolysaccharidosis III type C is caused by mutations in the HGSNAT gene leading to deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase involved in the lysosomal catabolism of heparan sulphate. To understand the pathophysiology of the disease we generated a mouse model of mucopolysaccharidosis III type C by germline inactivation of the Hgsnat gene. At 6-8 months mice showed hyperactivity, and reduced anxiety. Cognitive memory decline was detected at 10 months and at 12-13 months mice showed signs of unbalanced hesitant walk and urinary retention. Lysosomal accumulation of heparan sulphate was observed in hepatocytes, splenic sinus endothelium, cerebral microglia, liver Kupffer cells, fibroblasts and pericytes. Starting from 5 months, brain neurons showed enlarged, structurally abnormal mitochondria, impaired mitochondrial energy metabolism, and storage of densely packed autofluorescent material, gangliosides, lysozyme, phosphorylated tau, and amyloid-β. Taken together, our data demonstrate for the first time that deficiency of acetyl-CoA: α-glucosaminide N-acetyltransferase causes lysosomal accumulation of heparan sulphate in microglial cells followed by their activation and cytokine release. They also show mitochondrial dysfunction in the neurons and neuronal loss explaining why mucopolysaccharidosis III type C manifests primarily as a neurodegenerative disease.
authors.affiliation: 1 CHU Ste-Justine, University of Montreal, Montreal, QC, Canada.
authors.forename: Carla
authors.initials: C
authors.lastname: Martins
authors.affiliation: 2 Institute of Inherited Metabolic Disorders, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czech Republic.
authors.forename: Helena
authors.initials: H
authors.lastname: Hůlková
authors.affiliation: 1 CHU Ste-Justine, University of Montreal, Montreal, QC, Canada.
authors.forename: Larbi
authors.initials: L
authors.lastname: Dridi
authors.affiliation: 1 CHU Ste-Justine, University of Montreal, Montreal, QC, Canada.
authors.forename: Virginie
authors.initials: V
authors.lastname: Dormoy-Raclet
authors.affiliation: 1 CHU Ste-Justine, University of Montreal, Montreal, QC, Canada.
authors.forename: Lubov
authors.initials: L
authors.lastname: Grigoryeva
authors.affiliation: 1 CHU Ste-Justine, University of Montreal, Montreal, QC, Canada.
authors.forename: Yoo
authors.initials: Y
authors.lastname: Choi
authors.affiliation: 3 Stem Cell and Neurotherapies, University of Manchester, Manchester, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Langford-Smith
authors.affiliation: 3 Stem Cell and Neurotherapies, University of Manchester, Manchester, UK.
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Wilkinson
authors.affiliation: 4 Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ohmi
authors.affiliation: 1 CHU Ste-Justine, University of Montreal, Montreal, QC, Canada.
authors.forename: Graziella
authors.initials: G
authors.lastname: DiCristo
authors.affiliation: 5 Montreal Neurological Institute, McGill University, Montréal, QC, Canada.
authors.forename: Edith
authors.initials: E
authors.lastname: Hamel
authors.affiliation: 6 CHU Amiens, and Unité INSERM U1088, UFR de Médecine, Université de Picardie-Jules Verne, Amiens, France.
authors.forename: Jerôme
authors.initials: J
authors.lastname: Ausseil
authors.affiliation: 7 Service des Maladies Héréditaires du Métabolisme et Dépistage Néonatal - Centre de Biologie Est, Hospices Civils de Lyon, Bron, France.
authors.forename: David
authors.initials: D
authors.lastname: Cheillan
authors.affiliation: 1 CHU Ste-Justine, University of Montreal, Montreal, QC, Canada.
authors.forename: Alain
authors.initials: A
authors.lastname: Moreau
authors.affiliation: 2 Institute of Inherited Metabolic Disorders, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Svobodová
authors.affiliation: 8 Department of Paediatrics, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Hájková
authors.affiliation: 8 Department of Paediatrics, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czech Republic.
authors.forename: Markéta
authors.initials: M
authors.lastname: Tesařová
authors.affiliation: 8 Department of Paediatrics, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czech Republic.
authors.forename: Hana
authors.initials: H
authors.lastname: Hansíková
authors.affiliation: 3 Stem Cell and Neurotherapies, University of Manchester, Manchester, UK.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Bigger
authors.affiliation: 2 Institute of Inherited Metabolic Disorders, First Faculty of Medicine and General University Hospital in Prague, Charles University, Prague, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrebícek
authors.affiliation: 1 CHU Ste-Justine, University of Montreal, Montreal, QC, Canada alexei.pchejetski@umontreal.ca.
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Pshezhetsky
mesh_terms: D000123:Acetyltransferases / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D004734:Energy Metabolism / Q000502:physiology; D005732:Gangliosides / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000209:etiology / Q000473:pathology*; D009084:Mucopolysaccharidosis III / Q000150:complications / Q000473:pathology* / Q000523:psychology; D009443:Neuritis / Q000209:etiology / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000473:pathology* / Q000523:psychology; D009460:Neurologic Examination; D057165:Proteostasis Deficiencies / Q000473:pathology
chemical_list: D005732:Gangliosides; D006025:Glycosaminoglycans; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D000123:Acetyltransferases; C020580:glucosamine acetyltransferase
keywords: acetyl-CoA: α-glucosaminide N-acetyltransferase; glycosaminoglycans; heparan sulphate; knockout mouse model; mucopolysaccharidosis