Altered Differentiation Potential of Gaucher's Disease iPSC Neuronal Progenitors due to Wnt/β-Catenin Downregulation

Ola Awad, Leelamma M. Panicker, Rania M. Deranieh, Manasa P. Srikanth, Robert A. Brown, Antanina Voit, Tejasvi Peesay, Tea Soon Park, Elias Zambidis, Ricardo A. Feldman

Research output: Contribution to journalArticle

Abstract

Gaucher's disease (GD) is an autosomal recessive disorder caused by mutations in the GBA1 gene, which encodes acid β-glucocerebrosidase (GCase). Severe GBA1 mutations cause neuropathology that manifests soon after birth, suggesting that GCase deficiency interferes with neuronal development. We found that neuronopathic GD induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs) exhibit developmental defects due to downregulation of canonical Wnt/β-catenin signaling and that GD iPSCs’ ability to differentiate to dopaminergic (DA) neurons was strikingly reduced due to early loss of DA progenitors. Incubation of the mutant cells with the Wnt activator CHIR99021 (CHIR) or with recombinant GCase restored Wnt/β-catenin signaling and rescued DA differentiation. We also found that GD NPCs exhibit lysosomal dysfunction, which may be involved in Wnt downregulation by mutant GCase. We conclude that neuronopathic mutations in GCase lead to neurodevelopmental abnormalities due to a critical requirement of this enzyme for canonical Wnt/β-catenin signaling at early stages of neurogenesis. In this article, Feldman and colleagues describe a new mechanism linking severe GBA1 mutations to neurodevelopmental defects through Wnt/β-catenin downregulation. Using GD iPSCs as a model, the authors show that the ability of neuronopathic GD NPCs to differentiate to DA neurons is strikingly reduced due to early loss of DA progenitors and that lysosomal dysfunction may be directly involved in canonical Wnt downregulation.

Original languageEnglish (US)
Pages (from-to)1853-1867
Number of pages15
JournalStem Cell Reports
Volume9
Issue number6
DOIs
StatePublished - Dec 12 2017

Fingerprint

Gaucher Disease
Catenins
Induced Pluripotent Stem Cells
Glucosylceramidase
Stem cells
Down-Regulation
Mutation
Stem Cells
Dopaminergic Neurons
Neurons
Defects
Neurogenesis
Genes
Cells
Parturition
Acids
Enzymes

Keywords

  • dopaminergic development
  • Gaucher's disease
  • GBA1
  • glucocerebrosidase
  • iPSCs
  • lysosomal storage disease
  • neurodegeneration
  • neuronal progenitors
  • Wnt/β-catenin

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Awad, O., Panicker, L. M., Deranieh, R. M., Srikanth, M. P., Brown, R. A., Voit, A., ... Feldman, R. A. (2017). Altered Differentiation Potential of Gaucher's Disease iPSC Neuronal Progenitors due to Wnt/β-Catenin Downregulation. Stem Cell Reports, 9(6), 1853-1867. https://doi.org/10.1016/j.stemcr.2017.10.029

Altered Differentiation Potential of Gaucher's Disease iPSC Neuronal Progenitors due to Wnt/β-Catenin Downregulation. / Awad, Ola; Panicker, Leelamma M.; Deranieh, Rania M.; Srikanth, Manasa P.; Brown, Robert A.; Voit, Antanina; Peesay, Tejasvi; Park, Tea Soon; Zambidis, Elias; Feldman, Ricardo A.

In: Stem Cell Reports, Vol. 9, No. 6, 12.12.2017, p. 1853-1867.

Research output: Contribution to journalArticle

Awad, O, Panicker, LM, Deranieh, RM, Srikanth, MP, Brown, RA, Voit, A, Peesay, T, Park, TS, Zambidis, E & Feldman, RA 2017, 'Altered Differentiation Potential of Gaucher's Disease iPSC Neuronal Progenitors due to Wnt/β-Catenin Downregulation', Stem Cell Reports, vol. 9, no. 6, pp. 1853-1867. https://doi.org/10.1016/j.stemcr.2017.10.029
Awad, Ola ; Panicker, Leelamma M. ; Deranieh, Rania M. ; Srikanth, Manasa P. ; Brown, Robert A. ; Voit, Antanina ; Peesay, Tejasvi ; Park, Tea Soon ; Zambidis, Elias ; Feldman, Ricardo A. / Altered Differentiation Potential of Gaucher's Disease iPSC Neuronal Progenitors due to Wnt/β-Catenin Downregulation. In: Stem Cell Reports. 2017 ; Vol. 9, No. 6. pp. 1853-1867.
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AU - Brown, Robert A.

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AB - Gaucher's disease (GD) is an autosomal recessive disorder caused by mutations in the GBA1 gene, which encodes acid β-glucocerebrosidase (GCase). Severe GBA1 mutations cause neuropathology that manifests soon after birth, suggesting that GCase deficiency interferes with neuronal development. We found that neuronopathic GD induced pluripotent stem cell (iPSC)-derived neuronal progenitor cells (NPCs) exhibit developmental defects due to downregulation of canonical Wnt/β-catenin signaling and that GD iPSCs’ ability to differentiate to dopaminergic (DA) neurons was strikingly reduced due to early loss of DA progenitors. Incubation of the mutant cells with the Wnt activator CHIR99021 (CHIR) or with recombinant GCase restored Wnt/β-catenin signaling and rescued DA differentiation. We also found that GD NPCs exhibit lysosomal dysfunction, which may be involved in Wnt downregulation by mutant GCase. We conclude that neuronopathic mutations in GCase lead to neurodevelopmental abnormalities due to a critical requirement of this enzyme for canonical Wnt/β-catenin signaling at early stages of neurogenesis. In this article, Feldman and colleagues describe a new mechanism linking severe GBA1 mutations to neurodevelopmental defects through Wnt/β-catenin downregulation. Using GD iPSCs as a model, the authors show that the ability of neuronopathic GD NPCs to differentiate to DA neurons is strikingly reduced due to early loss of DA progenitors and that lysosomal dysfunction may be directly involved in canonical Wnt downregulation.

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