M-Y Son1,2, H Sim1,2, Y S Son1,2, K B Jung1,2, M-O Lee3, J-H Oh4,5, S-K Chung6, C-R Jung1,2, J Kim1,2. 1. Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea. 2. Department of functional genomics, University of Science & Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea. 3. Immunotherapy Convergence Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea. 4. Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea. 5. Department of human and environmental toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea. 6. Medical Research Division, Korea Institute of Oriental Medicine, Yuseong-gu, Daejeon, 34054, Republic of Korea.
Abstract
AIMS: The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic cause of Parkinson's disease (PD). There is compelling evidence that PD is not only a brain disease but also a gastrointestinal disorder; nonetheless, its pathogenesis remains unclear. We aimed to develop human neural and intestinal tissue models of PD patients harbouring an LRRK2 mutation to understand the link between LRRK2 and PD pathology by investigating the gene expression signature. METHODS: We generated PD patient-specific induced pluripotent stem cells (iPSCs) carrying an LRRK2 G2019S mutation (LK2GS) and then differentiated into three-dimensional (3D) human neuroectodermal spheres (hNESs) and human intestinal organoids (hIOs). To unravel the gene and signalling networks associated with LK2GS, we analysed differentially expressed genes in the microarray data by functional clustering, gene ontology (GO) and pathway analyses. RESULTS: The expression profiles of LK2GS were distinct from those of wild-type controls in hNESs and hIOs. The most represented GO biological process in hNESs and hIOs was synaptic transmission, specifically synaptic vesicle trafficking, some defects of which are known to be related to PD. The results were further validated in four independent PD-specific hNESs and hIOs by microarray and qRT-PCR analysis. CONCLUSION: We provide the first evidence that LK2GS also causes significant changes in gene expression in the intestinal cells. These hNES and hIO models from the same genetic background of PD patients could be invaluable resources for understanding PD pathophysiology and for advancing the complexity of in vitro models with 3D expandable organoids.
AIMS: The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic cause of Parkinson's disease (PD). There is compelling evidence that PD is not only a brain disease but also a gastrointestinal disorder; nonetheless, its pathogenesis remains unclear. We aimed to develop human neural and intestinal tissue models of PDpatients harbouring an LRRK2 mutation to understand the link between LRRK2 and PD pathology by investigating the gene expression signature. METHODS: We generated PDpatient-specific induced pluripotent stem cells (iPSCs) carrying an LRRK2G2019S mutation (LK2GS) and then differentiated into three-dimensional (3D) human neuroectodermal spheres (hNESs) and human intestinal organoids (hIOs). To unravel the gene and signalling networks associated with LK2GS, we analysed differentially expressed genes in the microarray data by functional clustering, gene ontology (GO) and pathway analyses. RESULTS: The expression profiles of LK2GS were distinct from those of wild-type controls in hNESs and hIOs. The most represented GO biological process in hNESs and hIOs was synaptic transmission, specifically synaptic vesicle trafficking, some defects of which are known to be related to PD. The results were further validated in four independent PD-specific hNESs and hIOs by microarray and qRT-PCR analysis. CONCLUSION: We provide the first evidence that LK2GS also causes significant changes in gene expression in the intestinal cells. These hNES and hIO models from the same genetic background of PDpatients could be invaluable resources for understanding PD pathophysiology and for advancing the complexity of in vitro models with 3D expandable organoids.
Authors: Nicholas J Fiore; Yosif M Ganat; Kapil Devkota; Rebecca Batorsky; Ming Lei; Kyongbum Lee; Lenore J Cowen; Gist Croft; Scott A Noggle; Thomas J F Nieland; David L Kaplan Journal: Cell Mol Life Sci Date: 2022-01-19 Impact factor: 9.261