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
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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