Neuroinflammation, mitochondrial defects and neurodegeneration in mucopolysaccharidosis III type C mouse model

Autor: David Cheillan, Helena Hůlková, Lubov S. Grigoryeva, Alain Moreau, Larbi Dridi, M. Hrebicek, Brian W. Bigger, Alex Langford-Smith, Zuzana Hájková, Alexey V. Pshezhetsky, Edith Hamel, Virginie Dormoy-Raclet, Kazuhiro Ohmi, Markéta Tesařová, Eva Svobodová, Jérôme Ausseil, Carla Martins, Hana Hansikova, Yoo Choi, Fiona L. Wilkinson, Graziella DiCristo
Přispěvatelé: Food and Nutrition Department, National Institute of Health Doutor Ricardo Jorge I.P, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA)
Jazyk: angličtina
Rok vydání: 2015
Předmět:
medicine.medical_specialty
Mucopolysaccharidosis
medicine.medical_treatment
[SDV]Life Sciences [q-bio]
Biology
Mitochondrion
Inbred C57BL
Gangliosides/metabolism
Energy Metabolism/physiology
Mice
Proteostasis Deficiencies/pathology
Mucopolysaccharidosis III
Internal medicine
medicine
Animals
Mitochondrial Diseases/etiology/*pathology
Neurodegenerative Diseases/etiology/*pathology/psychology
Glycosaminoglycans/metabolism
Neuroinflammation
Acetyltransferases/deficiency/genetics
Neurologic Examination
Behavior
Microglia
Catabolism
Animal
Neurodegeneration
Original Articles
medicine.disease
3. Good health
Cytokine
Endocrinology
medicine.anatomical_structure
Mucopolysaccharidosis III/complications/*pathology/psychology
Immunology
Microtubule-Associated Proteins/metabolism
Neurology (clinical)
Neuritis/etiology/*pathology
Zdroj: Brain-A Journal of Neurology
Brain-A Journal of Neurology, Oxford University Press (OUP), 2015, 138 (Pt 2), pp.336-55. ⟨10.1093/brain/awu355⟩
ISSN: 0006-8950
1460-2156
DOI: 10.1093/brain/awu355⟩
Popis: International audience; Severe progressive neurological paediatric disease mucopolysaccharidosis III type C is caused by mutations in the HGSNAT gene leading to deficiency of acetyl-CoA: alpha-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-beta. Taken together, our data demonstrate for the first time that deficiency of acetyl-CoA: alpha-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.
Databáze: OpenAIRE
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