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.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagosomes / genetics
  • Autophagosomes / metabolism*
  • Autophagosomes / ultrastructure
  • Autophagy / genetics*
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism
  • Axons / metabolism
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism
  • Developmental Disabilities / metabolism
  • Developmental Disabilities / physiopathology
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Fibroblasts / ultrastructure
  • Fingers / abnormalities*
  • Fingers / physiopathology
  • Gene Knockout Techniques
  • HeLa Cells
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • Intellectual Disability / metabolism*
  • Intellectual Disability / physiopathology
  • Microcephaly / metabolism*
  • Microcephaly / physiopathology
  • Microscopy, Electron
  • Muscle Hypotonia / metabolism*
  • Muscle Hypotonia / physiopathology
  • Mutation, Missense
  • Myopia / metabolism*
  • Myopia / physiopathology
  • Nerve Net / physiology
  • Neurons / metabolism*
  • Neurons / pathology
  • Obesity / metabolism*
  • Obesity / physiopathology
  • Retinal Degeneration / metabolism*
  • Retinal Degeneration / physiopathology
  • Up-Regulation
  • Vacuoles / metabolism
  • Vesicular Transport Proteins / genetics*


  • Autophagy-Related Proteins
  • VPS13B protein, human
  • Vesicular Transport Proteins
  • ATG4A protein, human
  • Cysteine Endopeptidases

Supplementary concepts

  • Cohen syndrome