HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B

Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which-through largely unknown mechanisms-can affect the brain where it clinically presents with microcephaly, intellectual disability and demyelination. Using human induced pluripotent stem cell (hiPSC)-derived neural 3D models generated from CSB patient-derived and isogenic control lines, we here provide explanations for these three major neuropathological phenotypes. In our models, CSB deficiency is associated with (i) impaired cellular migration due to defective autophagy as an explanation for clinical microcephaly; (ii) altered neuronal network functionality and neurotransmitter GABA levels, which is suggestive of a disturbed GABA switch that likely impairs brain circuit formation and ultimately causes intellectual disability; and (iii) impaired oligodendrocyte maturation as a possible cause of the demyelination observed in children with CSB. Of note, the impaired migration and oligodendrocyte maturation could both be partially rescued by pharmacological HDAC inhibition.

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Publication Details

Journal
Cellular and Molecular Life Sciences
Published
2024-08-23
DOI
https://doi.org/10.1007/s00018-024-05406-w
Citations
5
Primary Topic
Neurogenesis and neuroplasticity mechanisms
Type
article
Field-Weighted Citation Impact
2.06

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article

HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B

Katharina Koch, Gabriele Brockerhoff, Julia Kapr, Selina Dangeleit et al.
5 citations
Cellular and Molecular Life Sciences
Neurogenesis and neuroplasticity mechanisms
2.06
article

HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B

Katharina Koch, Gabriele Brockerhoff, Julia Kapr, Selina Dangeleit, Ellen Fritsche, Jean Krutmann, Haribaskar Ramachandran, Marius Pollet, Philipp Westhoff, Andrea Rossi, Ilka Scharkin
article en
5 citations

Abstract

Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which-through largely unknown mechanisms-can affect the brain where it clinically presents with microcephaly, intellectual disability and demyelination. Using human induced pluripotent stem cell (hiPSC)-derived neural 3D models generated from CSB patient-derived and isogenic control lines, we here provide explanations for these three major neuropathological phenotypes. In our models, CSB deficiency is associated with (i) impaired cellular migration due to defective autophagy as an explanation for clinical microcephaly; (ii) altered neuronal network functionality and neurotransmitter GABA levels, which is suggestive of a disturbed GABA switch that likely impairs brain circuit formation and ultimately causes intellectual disability; and (iii) impaired oligodendrocyte maturation as a possible cause of the demyelination observed in children with CSB. Of note, the impaired migration and oligodendrocyte maturation could both be partially rescued by pharmacological HDAC inhibition.

Cellular and Molecular Life SciencesVol. 81(1)
University of Basel (CH), Leibniz Institute of Environmental Medicine (DE), Cluster of Excellence on Plant Sciences (DE), Heinrich Heine University Düsseldorf (DE)
Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Heinrich-Heine-Universität Düsseldorf, Université de Lausanne, Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, Leibniz-Gemeinschaft
Openalex Percentile: Top 14%
Neurogenesis and neuroplasticity mechanisms
2.06
DOIOpen Access PDFOpenAlex
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