한빛사논문
Vincencius Vidyawan 1 2 †, Lesly Puspita 1 2 †, Virginia Blessy Juwono 1 2 †, Magdalena Deline 1 2, Kelvin Pieknell 3 4, Mi-Yoon Chang 3 4 5 6, Sang-Hun Lee 3 4 7 *, Jae-Won Shim 1 2 *
1Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan-Si, Korea.
2Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan-Si, Korea.
3Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea.
4Biomedical Research Institute, Hanyang University, Seoul, Korea.
5Department of Premedicine, College of Medicine, Hanyang University, Seoul, Korea.
6Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea.
7Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea.
†These authors contributed equally
*Corresponding authors: correspondence to Sang-Hun Lee or Jae-Won Shim
Abstract
Macroautophagy/autophagy dysregulation is associated with various neurological diseases, including Vici syndrome. We aimed to determine the role of autophagy in early brain development. We generated neurons from human embryonic stem cells and developed a Vici syndrome model by introducing a loss-of-function mutation in the EPG5 gene. Autophagy-related genes were upregulated at the neuronal progenitor cell stage. Inhibition of autolysosome formation with bafilomycin A1 treatment at the neuronal progenitor cell stage delayed neuronal differentiation. Notably, WNT (Wnt family member) signaling may be part of the underlying mechanism, which is negatively regulated by autophagy-mediated DVL2 (disheveled segment polarity protein 2) degradation. Disruption of autolysosome formation may lead to failure in the downregulation of WNT signaling, delaying neuronal differentiation. EPG5 mutations disturbed autolysosome formation, subsequently inducing defects in progenitor cell differentiation and cortical layer generation in organoids. Disrupted autophagy leads to smaller organoids, recapitulating Vici syndrome-associated microcephaly, and validating the disease relevance of our study.
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