Increased Neural Progenitor Proliferation in a hiPSC Model of Autism Induces Replication Stress-Associated Genome Instability
Open accessAbstract
The association between macrocephaly and autism spectrum disorder (ASD) suggests that the mechanisms underlying excessive neural growth could contribute to ASD pathogenesis. Consistently, neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) of ASD individuals with early developmental brain enlargement are inherently more proliferative than control NPCs. Here, we show that hiPSC-derived NPCs from ASD individuals with macrocephaly display an altered DNA replication program and increased DNA damage. When compared with the control NPCs, high-throughput genome-wide translocation sequencing (HTGTS) demonstrates that ASD-derived NPCs harbored elevated DNA double-strand breaks in replication stress-susceptible genes, some of which are associated with ASD pathogenesis. Our results provide a mechanism linking hyperproliferation of NPCs with the pathogenesis of ASD by disrupting long neural genes involved in cell-cell adhesion and migration.
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Some somatic mutations may underly neurodevelopmental and neurodegenerative disease.
“work has shown that some may underly neurodevelopmental and neurodegenerative disease.”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Wang et al, 2020
DSB hotspots reside in long genes that are important for neuronal function and are risk factors for autism spectrum disorder and schizophrenia.
“DSB hotspots reside in long genes that are important for neuronal function and are risk factors for autism spectrum disorder and schizophrenia”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Wang et al, 2020
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Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease
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- Authors
- Wang, M., Wei, P.-C., Lim, C. K., Gallina, I. S., Marshall, S., Marchetto, M. C., Alt, F. W., & Gage, F. H.
- Affiliations
- Salk Institute for Biological Studies (US)
- Boston Children's Hospital (US)
- Corresponding author
- Gage, Fred H.
- Venue
- Cell Stem Cell
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 26
- Issue
- 2
- Pages
- 221-233.e6
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- PMC
- PMC7175642
- OpenAlex
- W3003160292
- Cited by
- 105
- References
- 45
- Citations by year
- 2026: 10 · 2025: 22 · 2024: 17 · 2023: 16 · 2022: 15 · 2021: 15 · 2020: 9
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Leona M. and Harry B. Helmsley Charitable Trust
- American Heart Association
- National Institute of Mental Health
- JPB Foundation
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- autism spectrum disorder, neural progenitor cells, neural progenitor proliferation, macrocephaly, human induced pluripotent stem cells, replication stress, genomic instability, DNA double-strand breaks, DNA damage, cell-cell adhesion, cell migration
- MeSH terms
- Autism Spectrum Disorder, Autistic Disorder, Humans, Genomic Instability, Cell Proliferation, Induced Pluripotent Stem Cells
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