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Autophagy pathway upregulation in a human iPSC-derived neuronal model of Cohen syndrome with VPS13B missense mutations
- Source :
- Molecular Brain, Vol 13, Iss 1, Pp 1-4 (2020), Molecular Brain
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
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.
- Subjects :
- Autophagosome
Autophagosome organization
Developmental Disabilities
Induced Pluripotent Stem Cells
Mutation, Missense
Vesicular Transport Proteins
Autophagy-Related Proteins
Vacuole
Biology
lcsh:RC346-429
Micro Report
Fingers
Gene Knockout Techniques
Cellular and Molecular Neuroscience
Downregulation and upregulation
Intellectual Disability
VPS13B
Myopia
Autophagy
Humans
Obesity
Induced pluripotent stem cell
Molecular Biology
lcsh:Neurology. Diseases of the nervous system
Neurons
Vacuolar protein sorting
Cohen syndrome
iPSC
Retinal Degeneration
Autophagosomes
Fibroblasts
Axons
Up-Regulation
Cell biology
Cysteine Endopeptidases
Microscopy, Electron
Vacuoles
Microcephaly
Muscle Hypotonia
Nerve Net
HeLa Cells
Subjects
Details
- ISSN :
- 17566606
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Molecular Brain
- Accession number :
- edsair.doi.dedup.....8ca9d5593c47e40b1442fd008ffd8ab2