S4: Disease modeling of Parkinson’s Disease
Reprogramming and Differentiation for Disease modeling of Parkinson’s Disease
Stem Cell Research Center (SCRC)
Principal Investigator and Director
Reprogramming is a process in which a developmentally determined cell fate is re-established to another fate by artificial modifications. Because the genetic information is maintained unchanged after a reprogramming process, the reprogramming technology opens a new era of disease modeling and drug discovery by supplying intact patient-oriented cells which harbor genetic information of a patient. Reprogramming to the pluripotent state has been studied extensively in somatic cell nuclear transfer and induced pluripotent stem cells (iPSCs). Interestingly, recent studies showed that expression of a set of transcription factors also could induce transdifferentiation, also known as direct conversion or direct reprogramming. Parkinson’s disease (PD) is a progressive neurodegenerative disorder, affecting 1% of individuals over 60 years old and the second most common neurodegenerative disease after Alzheimer’s disease. For a better understanding of the pathophysiology of PD and more effective development of therapeutics of PD, we developed various reprogrammed cells related to PD and investigated application methods for PD-modeling. Among many PD-related genetic causes, Leucine-Rich Repeat Kinase 2 (LRRK2) G2019S mutation (LK2GS) which causes a constitutively active form of LRRK2 is the most common genetic cause of PD. Interestingly, we found LK2GS caused significant gene expression changes when the LK2GS-iPSCs were differentiated into three-dimensional (3D) neuroectodermal spheres (hNES) and intestinal organoids (hIO). We suggest that these 3D hNES and hIO models from the same iPSCs of PD patient could be invaluable resources for understanding PD pathophysiology in intestinal and neural tissues as well as provide a new paradigm for regenerative medicine as well as drug development for PD.