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Faster iPSC Generation May Allow Enhanced Disease Investigation and Therapeutic Screening

Review of "Synthetic mRNA-based differentiation method enables early detection of Parkinson's phenotypes in neurons derived from Gaucher disease iPS cells" from STEM CELLS Translational Medicine by Stuart P. Atkinson

Researchers from the laboratories of Tomohiko Akiyama (Keio University School of Medicine, Tokyo) and Hidehisa Iwata (Takeda Pharmaceutical Company Limited, Fujisawa, Japan) previously developed an efficient method to differentiate human induced pluripotent stem cells (iPSCs) into a range of cell types (including neurons [1]) through the transfection of synthetic mRNAs (synRNA) encoding transcription factor proteins. In a new STEM CELLS Translational Medicine article [2], the authors now employ their previously reported method to generate dopaminergic neurons [3] from type 1 Gaucher disease-specific iPSCs in the hope of building a platform to understand how this prevalent metabolic storage disorder disease [4, 5] leads to an increased lifetime risk of developing Parkinson's disease [6].

Mutations in the β‐glucocerebrosidase gene GBA1 cause type 1 Gaucher disease and induce the accumulation of glucosylceramide in affected cells, which may influence the formation of the α‐synuclein fibrils and soluble oligomers associated with Parkinson's disease development [7, 8]. Therefore, the authors began their study by concentrating on a study of glucosylceramide levels in type 1 Gaucher disease-iPSC-derived dopaminergic neurons by liquid chromatography‐mass spectrometry. Compared to a more conventional, yet more complex, method for the generation of mature dopaminergic neurons from iPSCs [9] that permitted the detection of glucosylceramide accumulation at sixty days, the synRNA methodology highlighted glucosylceramide accumulation after only ten days, a fact that may enable early detection of disease. Moreover, the study also detected an increase in phosphorylated α‐synuclein - a critical Parkinson's disease‐linked phenotype - in synRNA-generated type 1 Gaucher disease-iPSC-derived dopaminergic neurons. Interestingly, the authors demonstrated that the overexpression of wild‐type GBA1 or treatment with a glucosylceramide synthesis inhibitor (the ceramide analog DL-threo-PPMP) rescued this type 1 Gaucher disease-specific metabolic defect, while wild‐type GBA1 expression also significantly decreased the levels of phosphorylated α‐synuclein.

Overall, the authors present their synRNA methodology for dopaminergic neuron differentiation as a platform for the delineation of the various possible pathological mechanisms associated with Parkinson's disease onset in GD1 patients and the rapid exploration of possible treatment options.

For more on how the synthetic mRNA-mediated differentiation of human iPSCs may represent the future of disease investigation and therapeutic screening, stay tuned to the Stem Cells Portal!


References

  1. Goparaju SK, Kohda K, Ibata K, et al., Rapid differentiation of human pluripotent stem cells into functional neurons by mRNAs encoding transcription factors. Scientific Reports 2017;7:42367.
  2. Akiyama T, Sato S, Ko SBH, et al., Synthetic mRNA-based differentiation method enables early detection of Parkinson's phenotypes in neurons derived from Gaucher disease-induced pluripotent stem cells. STEM CELLS Translational Medicine 2021;10:572-581.
  3. Arenas E, Denham M, and Villaescusa JC, How to make a midbrain dopaminergic neuron. Development 2015;142:1918.
  4. Jmoudiak M and Futerman AH, Gaucher disease: pathological mechanisms and modern management. British Journal of Haematology 2005;129:178-188.
  5. Sidransky E, Gaucher disease: complexity in a “simple” disorder. Molecular Genetics and Metabolism 2004;83:6-15.
  6. Bultron G, Kacena K, Pearson D, et al., The risk of Parkinson's disease in type 1 Gaucher disease. Journal of Inherited Metabolic Disease 2010;33:167-173.
  7. Mazzulli Joseph R, Xu Y-H, Sun Y, et al., Gaucher Disease Glucocerebrosidase and α-Synuclein Form a Bidirectional Pathogenic Loop in Synucleinopathies. Cell 2011;146:37-52.
  8. Suzuki M, Fujikake N, Takeuchi T, et al., Glucocerebrosidase deficiency accelerates the accumulation of proteinase K-resistant α-synuclein and aggravates neurodegeneration in a Drosophila model of Parkinson's disease. Human Molecular Genetics 2015;24:6675-6686.
  9. Kriks S, Shim J-W, Piao J, et al., Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson’s disease. Nature 2011;480:547-551.