Back to Search
Start Over
Synthetic mRNA‐based differentiation method enables early detection of Parkinson's phenotypes in neurons derived from Gaucher disease‐induced pluripotent stem cells
- Source :
- Stem Cells Translational Medicine, Stem Cells Translational Medicine, Vol 10, Iss 4, Pp 572-581 (2021)
- Publication Year :
- 2020
- Publisher :
- John Wiley & Sons, Inc., 2020.
-
Abstract
- Gaucher disease, the most prevalent metabolic storage disorder, is caused by mutations in the glucocerebrosidase gene GBA1, which lead to the accumulation of glucosylceramide (GlcCer) in affected cells. Gaucher disease type 1 (GD1), although defined as a nonneuronopathic subtype, is accompanied by an increased risk of Parkinson's disease. To gain insights into the association of progressive accumulation of GlcCer and the Parkinson's disease phenotypes, we generated dopaminergic (DA) neurons from induced pluripotent stem cells (iPSCs) derived from a GD1 patient and a healthy donor control, and measured GlcCer accumulation by liquid chromatography‐mass spectrometry. We tested two DA neuron differentiation methods: a well‐established method that mimics a step‐wise developmental process from iPSCs to neural progenitor cells, and to DA neurons; and a synthetic mRNA‐based method that overexpresses a transcription factor in iPSCs. GD1‐specific accumulation of GlcCer was detected after 60 days of differentiation by the former method, whereas it was detected after only 10 days by the latter method. With this synthetic mRNA‐based rapid differentiation method, we found that the metabolic defect in GD1 patient cells can be rescued by the overexpression of wild‐type GBA1 or the treatment with an inhibitor for GlcCer synthesis. Furthermore, we detected the increased phosphorylation of α‐synuclein, a biomarker for Parkinson's disease, in DA neurons derived from a GD1 patient, which was significantly decreased by the overexpression of wild‐type GBA1. These results suggest that synthetic mRNA‐based method accelerates the analyses of the pathological mechanisms of Parkinson's disease in GD1 patients and possibly facilitates drug discovery processes.<br />Synthetic mRNA‐based expression of transcription factors enhanced induced pluripotent stem cell differentiation and enabled early (10 days) detection of a risk factor of Parkinson's disease, i.e. the accumulation of glucosylceramide (GlcCer) in Gaucher patient neurons. This rapid differentiation method also enabled to detect the phosphorylation of α‐synuclein—a critical Parkinson's disease‐linked phenotype.
- Subjects :
- 0301 basic medicine
Pluripotent Stem Cells
Parkinson's disease
neural differentiation
Induced Pluripotent Stem Cells
Biology
03 medical and health sciences
0302 clinical medicine
transcription factors
medicine
Humans
RNA, Messenger
lcsh:QH573-671
Induced pluripotent stem cell
Transcription factor
lcsh:R5-920
Gaucher Disease
lcsh:Cytology
Dopaminergic Neurons
Dopaminergic
Cell Differentiation
Parkinson Disease
Cell Biology
General Medicine
differentiation
medicine.disease
Phenotype
Neural stem cell
Cell biology
030104 developmental biology
Neuron differentiation
induced pluripotent stem cells (iPSCs)
lcsh:Medicine (General)
Glucocerebrosidase
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 21576580 and 21576564
- Volume :
- 10
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Stem Cells Translational Medicine
- Accession number :
- edsair.doi.dedup.....256aad67d4de364472b92a22ed24445f