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Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson's disease-linked DNAJC6 mutations

Title
Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson's disease-linked DNAJC6 mutations
Author
장미윤
Issue Date
2021-02
Publisher
AMER ASSOC ADVANCEMENT SCIENCE
Citation
SCIENCE ADVANCES, v. 7, no. 8, article no. eabb1540, Page. 1-18
Abstract
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.
URI
https://www.science.org/doi/10.1126/sciadv.abb1540https://repository.hanyang.ac.kr/handle/20.500.11754/175641
ISSN
2375-2548
DOI
10.1126/sciadv.abb1540
Appears in Collections:
COLLEGE OF MEDICINE[S](의과대학) > PRE-MEDICINE(의예과) > Articles
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