Lysosomal and network alterations in human mucopolysaccharidosis type VII iPSC-derived neurons
| Autor: | Marina Lavigne, Christina Begon-Pescia, Eric J. Kremer, Philippe Lory, Antonella Consiglio, Sara Salinas, Assumpció Bosch, Sophie Creyssels, Ana Maria Cuervo, Daniel Simão, Neus Bayó-Puxan, Florence Bernex, Thierry Levade, Vasiliki Kalatzis, Ana Paula Terrasso, Catarina Brito |
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| Přispěvatelé: | Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Instituto de Biologia Experimental e Tecnológica (IBET), Instituto de Tecnologia Química e Biológica António Xavier (ITQB), Universidade Nova de Lisboa (NOVA), Pathogénèse et contrôle des infections chroniques (PCCI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre Hospitalier Universitaire de Montpellier (CHU Montpellier ), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), BioCampus Montpellier (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona [Barcelona] (UAB), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Albert Einstein College of Medicine, Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Department of Molecular and Translational Medicine, University of Brescia, Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Universitat Autònoma de Barcelona (UAB), Albert Einstein College of Medicine [New York] |
| Rok vydání: | 2018 |
| Předmět: |
Case-Control Studies
Cell Differentiation Cells Cultured Glycosaminoglycans Humans Induced Pluripotent Stem Cells Lysosomes Mucopolysaccharidosis VII Neurons Stem Cells Neural Pathways Lysosomal Storage Disorders (LSD) 0301 basic medicine Cells [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Mucopolysaccharidosis lcsh:Medicine Mucopolysaccharides Biology Article Lipofuscin Lysosome-associated Membrane Protein (LAMP1) 03 medical and health sciences Cognition SDG 3 - Good Health and Well-being Downregulation and upregulation Lysosome Lysosomal storage disease medicine Premovement neuronal activity GABAergic Neurons General lcsh:Science Cultured Multidisciplinary lcsh:R Enzyme replacement therapy medicine.disease 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure Mucopolisacàrids EGFR Degradation Ipsc Clones Cognició lcsh:Q Astrocyte |
| Zdroj: | Scientific Reports Scientific Reports, Nature Publishing Group, 2018, 8, pp.16644. ⟨10.1038/s41598-018-34523-3⟩ SCIENTIFIC REPORTS r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu Fundació Sant Joan de Déu Dipòsit Digital de la UB Universidad de Barcelona Scientific Reports, Vol 8, Iss 1, Pp 1-19 (2018) Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu instname |
| ISSN: | 2045-2322 |
| Popis: | International audience; Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by deficient β-glucuronidase (β-gluc) activity. Significantly reduced β-gluc activity leads to accumulation of glycosaminoglycans (GAGs) in many tissues, including the brain. Numerous combinations of mutations in GUSB (the gene that codes for β-gluc) cause a range of neurological features that make disease prognosis and treatment challenging. Currently, there is little understanding of the molecular basis for MPS VII brain anomalies. To identify a neuronal phenotype that could be used to complement genetic analyses, we generated two iPSC clones derived from skin fibroblasts of an MPS VII patient. We found that MPS VII neurons exhibited reduced β-gluc activity and showed previously established disease-associated phenotypes, including GAGs accumulation, expanded endocytic compartments, accumulation of lipofuscin granules, more autophagosomes, and altered lysosome function. Addition of recombinant β-gluc to MPS VII neurons, which mimics enzyme replacement therapy, restored disease-associated phenotypes to levels similar to the healthy control. MPS VII neural cells cultured as 3D neurospheroids showed upregulated GFAP gene expression, which was associated with astrocyte reactivity, and downregulation of GABAergic neuron markers. Spontaneous calcium imaging analysis of MPS VII neurospheroids showed reduced neuronal activity and altered network connectivity in patient-derived neurospheroids compared to a healthy control. These results demonstrate the interplay between reduced β-gluc activity, GAG accumulation and alterations in neuronal activity, and provide a human experimental model for elucidating the bases of MPS VII-associated cognitive defects. Lysosomal storage disorders (LSD) are caused by intra-and extracellular accumulation of undigested macromol-ecules that induce dysfunction of the greater lysosomal system. Among LSD, mucopolysaccharidoses (MPS) are caused by deficiency in enzymatic activities that degrade glycosaminoglycans (GAGs). GAGs are the most abundant polysaccharides of the extracellular matrix (ECM) and, with the exception of hyaluronic acid, are covalently attached to protein moieties to form proteoglycans 1. β-glucuronidase (β-gluc, EC 3.2.1.31), is found in lysosomes |
| Databáze: | OpenAIRE |
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