Wulansari, Noviana Darsono, Wahyu Handoko Wibowo Woo, Hye-Ji Chang, Mi-Yoon Kim, Jinil Bae, Eun-Jin Sun, Woong Lee, Ju-Hyun Cho, Il-Joo Shin, Hyogeun Lee, Seung-Jae Lee, Sang-Hun 2024-01-19T15:31:53Z 2024-01-19T15:31:53Z 2021-10-21 2021-02 2375-2548 https://pubs.kist.re.kr/handle/201004/117449 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 alpha-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. English AMER ASSOC ADVANCEMENT SCIENCE Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson's disease-linked DNAJC6 mutations Article 10.1126/sciadv.abb1540 1 SCIENCE ADVANCES, v.7, no.8 SCIENCE ADVANCES 7 8 N scie scopus 000620146100001 2-s2.0-85101415683 Multidisciplinary Sciences Science & Technology - Other Topics Article GENE-EXPRESSION STEM-CELLS MIDBRAIN NURR1 CLATHRIN FOXA2 LMX1B DIFFERENTIATION ALPHA-SYNUCLEIN DOPAMINERGIC-NEURONS