| Literature DB >> 31750563 |
Mi-Yoon Chang1,2, Boram Oh1,2,3, Jang-Eun Choi1,2,3, Yanuar Alan Sulistio1,2,3, Hye-Ji Woo1,2,3, Ayoung Jo1,2, Jinil Kim1,2,3, Eun-Hee Kim1,2,3, Seung Won Kim1,2,3, Jungwook Hwang2,3, Jungyun Park2,3, Jae-Jin Song1,2,3, Oh-Chan Kwon1,2,3, Hyongbum Henry Kim4, Young-Hoon Kim4, Joo Yeon Ko5, Jun Young Heo6, Min Joung Lee6, Moses Lee7, Murim Choi7, Sun Ju Chung8, Hyun-Seob Lee9,10, Sang-Hun Lee1,2,3.
Abstract
Parkinson's disease (PD) is neurodegenerative movement disorder characterized by degeneration of midbrain-type dopamine (mDA) neurons in the substantia nigra (SN). The RNA-binding protein Lin28 plays a role in neuronal stem cell development and neuronal differentiation. In this study, we reveal that Lin28 conditional knockout (cKO) mice show degeneration of mDA neurons in the SN, as well as PD-related behavioral deficits. We identify a loss-of-function variant of LIN28A (R192G substitution) in two early-onset PD patients. Using an isogenic human embryonic stem cell (hESC)/human induced pluripotent stem cell (hiPSC)-based disease model, we find that the Lin28 R192G variant leads to developmental defects and PD-related phenotypes in mDA neuronal cells that can be rescued by expression of wild-type Lin28A. Cell transplantation experiments in PD model rats show that correction of the LIN28A variant in the donor patient (pt)-hiPSCs leads to improved behavioral phenotypes. Our data link LIN28A to PD pathogenesis and suggest future personalized medicine targeting this variant in patients.Entities:
Keywords: Lin28; Parkinson's disease; human disease model; human pluripotent stem cells; loss-of-function mutation
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Year: 2019 PMID： 31750563 PMCID： PMC6912061 DOI： 10.15252/embj.2018101196
Source DB: PubMed Journal: EMBO J ISSN： 0261-4189 Impact factor: 11.598