2. Academic Validation
  3. Autophagy pathway upregulation in a human iPSC-derived neuronal model of Cohen syndrome with VPS13B missense mutations

Autophagy pathway upregulation in a human iPSC-derived neuronal model of Cohen syndrome with VPS13B missense mutations

  • Mol Brain. 2020 May 6;13(1):69. doi: 10.1186/s13041-020-00611-7.
You-Kyung Lee 1,  Soo-Kyeong Lee 1,  Suin Choi 1 2,  Yang Hoon Huh 2,  Ji-Hye Kwak 3,  Yong-Seok Lee 4,  Deok-Jin Jang 5,  Jae-Hyung Lee 6,  Kyungmin Lee 3,  Bong-Kiun Kaang 7,  Chae-Seok Lim 8,  Jin-A Lee 9
Affiliations

Affiliations

  • 1 Department of Biological Sciences and Biotechnology, Hannam University, 1646 Yuseongdaero, Yuseong-gu, Daejeon, 34054, Korea.
  • 2 Center for Electron Microscopy Research, Korea Basic Science Institute, Daejeon, 34133, Korea.
  • 3 Department of Anatomy, Brain Science & Engineering Institute, Kyungpook National University School of Medicine, Daegu, 41944, Korea.
  • 4 Department of Physiology, Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea.
  • 5 Department of Ecological Science, College of Ecology and Environmental Science, Kyungpook National University, Sangju, 37224, Korea.
  • 6 Department of Life and Nanopharmaceutical Sciences, Department of Oral Microbiology, School of Dentistry, Kyung Hee University, Seoul, 02447, Korea.
  • 7 Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, 08826, Korea.
  • 8 Department of Pharmacology, Wonkwang University School of Medicine, 460 Iksan-daero, Iksan, 54538, Korea. cslimwk1@wku.ac.kr.
  • 9 Department of Biological Sciences and Biotechnology, Hannam University, 1646 Yuseongdaero, Yuseong-gu, Daejeon, 34054, Korea. leeja@hnu.kr.
PMID: 32375900 DOI: 10.1186/s13041-020-00611-7
Abstract

Significant clinical symptoms of Cohen syndrome (CS), a rare autosomal recessive disorder, include intellectual disability, facial dysmorphism, postnatal microcephaly, retinal dystrophy, and intermittent neutropenia. CS has been associated with mutations in the VPS13B (vacuolar protein sorting 13 homolog B) gene, which regulates vesicle-mediated protein sorting and transport; however, the cellular mechanism underlying CS pathogenesis in patient-derived neurons remains uncertain. This report states that autophagic vacuoles accumulate in CS fibroblasts and the axonal terminals of CS patient-specific induced pluripotent stem cells (CS iPSC)-derived neurons; additionally, autophagic flux was significantly increased in CS-derived neurons compared to control neurons. VPS13B knockout HeLa cell lines generated using the CRISPR/Cas9 genome editing system showed significant upregulation of autophagic flux, indicating that VSP13B may be associated with Autophagy in CS. Transcriptomic analysis focusing on the Autophagy pathway revealed that genes associated with autophagosome organization were dysregulated in CS-derived neurons. ATG4C is a mammalian Atg4 paralog and a crucial regulatory component of the autophagosome biogenesis/recycling pathway. ATG4C was significantly upregulated in CS-derived neurons, indicating that Autophagy is upregulated in CS neurons. The Autophagy pathway in CS neurons may be associated with the pathophysiology exhibited in the neural network of CS patients.

Keywords

Autophagy; Cohen syndrome; VPS13B; iPSC.

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