TY - JOUR
T1 - Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson's disease-linked DNAJC6 mutations
AU - Wulansari, Noviana
AU - Darsono, Wahyu Handoko Wibowo
AU - Woo, Hye Ji
AU - Chang, Mi Yoon
AU - Kim, Jinil
AU - Bae, Eun Jin
AU - Sun, Woong
AU - Lee, Ju Hyun
AU - Cho, Il Joo
AU - Shin, Hyogeun
AU - Lee, Seung Jae
AU - Lee, Sang Hun
N1 - Funding Information:
This work was supported by the grants 2017R1A5A2015395, 2017M3A9B4062415, and 2020M3A9D8039925 (to S.-H.L.); NRF-2018R1A5A2025964 (to S.-J.L); and NRF-2020R1l1A1A01072544 (to N.W.) funded by the National Research Foundation of Korea (NRF) of the Ministry of Science and ICT, Republic of Korea.
Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/2/17
Y1 - 2021/2/17
N2 - Loss-of-function mutations of DNAJC6, encoding HSP40 auxilin, have recently been identified in patients with early-onset Parkinson's disease (PD). To study the roles of DNAJC6 in PD pathogenesis, we used human embryonic stem cells with CRISPR-Cas9-mediated gene editing. Here, we show that DNAJC6 mutations cause key PD pathologic features, i.e., midbrain-type dopamine (mDA) neuron degeneration, pathologic α-synuclein aggregation, increase of intrinsic neuronal firing frequency, and mitochondrial and lysosomal dysfunctions in human midbrain-like organoids (hMLOs). In addition, neurodevelopmental defects were also manifested in hMLOs carrying the mutations. Transcriptomic analyses followed by experimental validation revealed that defects in DNAJC6-mediated endocytosis impair the WNT-LMX1A signal during the mDA neuron development. Furthermore, reduced LMX1A expression during development caused the generation of vulnerable mDA neurons with the pathologic manifestations. These results suggest that the human model of DNAJC6-PD recapitulates disease phenotypes and reveals mechanisms underlying disease pathology, providing a platform for assessing therapeutic interventions.
AB - Loss-of-function mutations of DNAJC6, encoding HSP40 auxilin, have recently been identified in patients with early-onset Parkinson's disease (PD). To study the roles of DNAJC6 in PD pathogenesis, we used human embryonic stem cells with CRISPR-Cas9-mediated gene editing. Here, we show that DNAJC6 mutations cause key PD pathologic features, i.e., midbrain-type dopamine (mDA) neuron degeneration, pathologic α-synuclein aggregation, increase of intrinsic neuronal firing frequency, and mitochondrial and lysosomal dysfunctions in human midbrain-like organoids (hMLOs). In addition, neurodevelopmental defects were also manifested in hMLOs carrying the mutations. Transcriptomic analyses followed by experimental validation revealed that defects in DNAJC6-mediated endocytosis impair the WNT-LMX1A signal during the mDA neuron development. Furthermore, reduced LMX1A expression during development caused the generation of vulnerable mDA neurons with the pathologic manifestations. These results suggest that the human model of DNAJC6-PD recapitulates disease phenotypes and reveals mechanisms underlying disease pathology, providing a platform for assessing therapeutic interventions.
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U2 - 10.1126/sciadv.abb1540
DO - 10.1126/sciadv.abb1540
M3 - Article
C2 - 33597231
AN - SCOPUS:85101415683
VL - 7
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 8
M1 - eabb1540
ER -