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Lysosomal and network alterations in human mucopolysaccharidosis type VII iPSC-derived neurons

2018-12-01Artigo científico Acesso aberto
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dc.contributor.authorBayó-Puxan, Neus
dc.contributor.authorTerrasso, Ana Paula
dc.contributor.authorCreyssels, Sophie
dc.contributor.authorSimão, Daniel
dc.contributor.authorBegon-Pescia, Christina
dc.contributor.authorLavigne, Marina
dc.contributor.authorSalinas, Sara
dc.contributor.authorBernex, Florence
dc.contributor.authorBosch, Assumpció
dc.contributor.authorKalatzis, Vasiliki
dc.contributor.authorLevade, Thierry
dc.contributor.authorCuervo, Ana Maria
dc.contributor.authorLory, Philippe
dc.contributor.authorConsiglio, Antonella
dc.contributor.authorBrito, Catarina
dc.contributor.authorKremer, Eric J.
dc.contributor.institutionInstituto de Tecnologia Química e Biológica António Xavier (ITQB)
dc.contributor.pblNature Publishing Group
dc.date.accessioned2019-04-29T22:16:37Z
dc.date.available2019-04-29T22:16:37Z
dc.date.issued2018-12-01
dc.description.abstractMucopolysaccharidosis 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.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent8642939
dc.identifier.doi10.1038/s41598-018-34523-3
dc.identifier.issn2045-2322
dc.identifier.otherPURE: 12287678
dc.identifier.otherPURE UUID: 68f42751-34fe-46f7-9c65-b80787599a65
dc.identifier.otherScopus: 85056260796
dc.identifier.otherPubMed: 30413728
dc.identifier.urihttp://www.scopus.com/inward/record.url?scp=85056260796&partnerID=8YFLogxK
dc.identifier.urihttps://www.nature.com/articles/s41598-018-34523-3.pdf
dc.identifier.urlhttps://www.scopus.com/pages/publications/85056260796
dc.identifier.urlhttps://www.nature.com/articles/s41598-018-34523-3.pdf
dc.language.isoeng
dc.peerreviewedyes
dc.subjectGeneral
dc.subjectSDG 3 - Good Health and Well-being
dc.titleLysosomal and network alterations in human mucopolysaccharidosis type VII iPSC-derived neuronsen
dc.typejournal article
degois.publication.issue1
degois.publication.titleScientific Reports
degois.publication.volume8
dspace.entity.typePublication
rcaap.rightsopenAccess

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