title: Distinctive genomic signature of neural and intestinal organoids from familial Parkinson's disease patient-derived induced pluripotent stem cells.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.|Department of functional genomics, University of Science & Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
authors.forename: M-Y
authors.initials: MY
authors.lastname: Son
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.|Department of functional genomics, University of Science & Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
authors.forename: H
authors.initials: H
authors.lastname: Sim
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.|Department of functional genomics, University of Science & Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
authors.forename: Y S
authors.initials: YS
authors.lastname: Son
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.|Department of functional genomics, University of Science & Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
authors.forename: K B
authors.initials: KB
authors.lastname: Jung
authors.affiliation: Immunotherapy Convergence Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
authors.forename: M-O
authors.initials: MO
authors.lastname: Lee
authors.affiliation: Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.|Department of human and environmental toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Oh
authors.affiliation: Medical Research Division, Korea Institute of Oriental Medicine, Yuseong-gu, Daejeon, 34054, Republic of Korea.
authors.forename: S-K
authors.initials: SK
authors.lastname: Chung
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.|Department of functional genomics, University of Science & Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
authors.forename: C-R
authors.initials: CR
authors.lastname: Jung
authors.affiliation: Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.|Department of functional genomics, University of Science & Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon, 34113, Republic of Korea.
authors.forename: J
authors.identifier: http://orcid.org/0000-0003-3227-958X
authors.initials: J
authors.lastname: Kim
mesh_terms: D000328:Adult; D002454:Cell Differentiation; D005260:Female; D015870:Gene Expression; D063990:Gene Ontology; D016678:Genome; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009940:Organoids / Q000166:cytology / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics*
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
keywords: LRRK2; Parkinson's disease; induced pluripotent stem cell; intestinal organoid; microarray; neural progenitor cell; neuroectodermal sphere