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.

CHU Amiens and Unité INSERM U1088 UFR de Médecine Université de Picardie Jules Verne Amiens France

CHU Ste Justine University of Montreal Montreal QC Canada

Department of Biological Chemistry David Geffen School of Medicine University of California Los Angeles Los Angeles California USA

Department of Paediatrics 1st Faculty of Medicine and General University Hospital Prague Charles University Prague Czech Republic

Institute of Inherited Metabolic Disorders 1st Faculty of Medicine and General University Hospital Prague Charles University Prague Czech Republic

Montreal Neurological Institute McGill University Montréal QC Canada

Service des Maladies Héréditaires du Métabolisme et Dépistage Néonatal Centre de Biologie Est Hospices Civils de Lyon Bron France

Stem Cell and Neurotherapies University of Manchester Manchester UK

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Brain. 2015 Jul;138(Pt 7):e366. doi: 10.1093/brain/awv035. PubMed

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