Induced Pluripotent Stem Cells to Understand Mucopolysaccharidosis. I: Demonstration of a Migration Defect in Neural Precursors
Autor: | Antoine Marteyn, Adama Sidibé, Matthias R. Baumgartner, Karl-Heinz Krause, Sten Ilmjärv, Patricie Burda, Bernhard Wehrle-Haller, Silvin Lito |
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Přispěvatelé: | University of Zurich |
Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Mucopolysaccharidosis Mucopolysaccharidosis I Neurons/metabolism Gene Expression 2700 General Medicine ddc:616.07 Iduronidase 0302 clinical medicine Cell Movement Gene expression Iduronidase/genetics/metabolism Induced pluripotent stem cell lcsh:QH301-705.5 Cells Cultured Glycosaminoglycans Neurons Cultured Neurodegeneration Cell Differentiation General Medicine Phenotype Cell biology Lysosomes/genetics/metabolism neurite outgrowth Mutation/genetics induced pluripotent stem cells Cells Cell Differentiation/genetics 610 Medicine & health Biology Article neural migration 03 medical and health sciences medicine Cell Movement/genetics Glycosaminoglycans/genetics/metabolism Humans Allele ddc:612 Gene neuronal differentiation medicine.disease disease modelling Gene Expression/genetics Induced Pluripotent Stem Cells/metabolism 030104 developmental biology lcsh:Biology (General) 10036 Medical Clinic Mutation Lysosomes 030217 neurology & neurosurgery Mucopolysaccharidosis I/genetics/metabolism |
Zdroj: | Cells Volume 9 Issue 12 Cells, Vol. 9, No 12 (2020) P. 2593 Cells, Vol 9, Iss 2593, p 2593 (2020) |
ISSN: | 2073-4409 |
Popis: | Background: Mucopolysaccharidosis type I-Hurler (MPS1-H) is a severe genetic lysosomal storage disorder due to loss-of-function mutations in the IDUA gene. The subsequent complete deficiency of alpha l-iduronidase enzyme is directly responsible of a progressive accumulation of glycosaminoglycans (GAG) in lysosomes which affects the functions of many tissues. Consequently, MPS1 is characterized by systemic symptoms (multiorgan dysfunction) including respiratory and cardiac dysfunctions, skeletal abnormalities and early fatal neurodegeneration. Methods: To understand mechanisms underlying MPS1 neuropathology, we generated induced pluripotent stem cells (iPSC) from a MPS1-H patient with loss-of-function mutations in both IDUA alleles. To avoid variability due to different genetic background of iPSC, we established an isogenic control iPSC line by rescuing IDUA expression by a lentivectoral approach. Results: Marked differences between MPS1-H and IDUA-corrected isogenic controls were observed upon neural differentiation. A scratch assay revealed a strong migration defect of MPS1-H cells. Also, there was a massive impact of IDUA deficiency on gene expression (340 genes with an FDR < 0.05). Conclusions: Our results demonstrate a hitherto unknown connection between lysosomal degradation, gene expression and neural motility, which might account at least in part for the phenotype of MPS1-H patients. |
Databáze: | OpenAIRE |
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