LIN28A Loss of Function is Associated with Parkinson's Disease Pathogenesis

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2019 Nov 22

PMID 31750563

Citations 21

Authors

Mi-Yoon Chang

Boram Oh

Jang-Eun Choi

Yanuar Alan Sulistio

Hye-Ji Woo

Ayoung Jo

Jinil Kim

Eun-Hee Kim

Seung Won Kim

Jungwook Hwang

Jungyun Park

Jae-Jin Song

Oh-Chan Kwon

Hyongbum Henry Kim

Young-Hoon Kim

Joo Yeon Ko

Jun Young Heo

Min Joung Lee

Moses Lee

Murim Choi

Sun Ju Chung

Hyun-Seob Lee

Sang-Hun Lee

Affiliations

Soon will be listed here.

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.

Citing Articles

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