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HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B
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HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B
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Journal Article
HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B
2024
Overview
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.
Graphical Abstract
Publisher
Springer International Publishing,Springer Nature B.V
Subject
/ Biomedical and Life Sciences
/ Brain
/ Cloning
/ Cockayne Syndrome - genetics
/ Cockayne Syndrome - metabolism
/ Cockayne Syndrome - pathology
/ CRISPR
/ Demyelinating Diseases - metabolism
/ Demyelinating Diseases - pathology
/ Design
/ Disease
/ DNA Repair Enzymes - genetics
/ DNA Repair Enzymes - metabolism
/ gamma-Aminobutyric Acid - metabolism
/ Humans
/ Induced Pluripotent Stem Cells - cytology
/ Induced Pluripotent Stem Cells - metabolism
/ Induced Pluripotent Stem Cells - pathology
/ neurons
/ Oligodendroglia - metabolism
/ Poly-ADP-Ribose Binding Proteins - genetics
