Cockayne syndrome-derived neurons display reduced synapse density and altered neural network synchrony

Hum Mol Genet. 2016 Apr 1;25(7):1271-80. doi: 10.1093/hmg/ddw008. Epub 2016 Jan 10.


Cockayne syndrome (CS) is a rare genetic disorder in which 80% of cases are caused by mutations in the Excision Repair Cross-Complementation group 6 gene (ERCC6). The encoded ERCC6 protein is more commonly referred to as Cockayne Syndrome B protein (CSB). Classical symptoms of CS patients include failure to thrive and a severe neuropathology characterized by microcephaly, hypomyelination, calcification and neuronal loss. Modeling the neurological aspect of this disease has proven difficult since murine models fail to mirror classical neurological symptoms. Therefore, a robust human in vitro cellular model would advance our fundamental understanding of the disease and reveal potential therapeutic targets. Herein, we successfully derived functional CS neural networks from human CS induced pluripotent stem cells (iPSCs) providing a new tool to facilitate studying this devastating disease. We identified dysregulation of the Growth Hormone/Insulin-like Growth Factor-1 (GH/IGF-1) pathway as well as pathways related to synapse formation, maintenance and neuronal differentiation in CSB neurons using unbiased RNA-seq gene expression analyses. Moreover, when compared to unaffected controls, CSB-deficient neural networks displayed altered electrophysiological activity, including decreased synchrony, and reduced synapse density. Collectively, our work reveals that CSB is required for normal neuronal function and we have established an alternative to previously available models to further study neural-specific aspects of CS.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Cell Differentiation
  • Cell Line
  • Child
  • Child, Preschool
  • Cockayne Syndrome / genetics
  • Cockayne Syndrome / metabolism
  • Cockayne Syndrome / physiopathology*
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA Repair
  • DNA Repair Enzymes / genetics
  • DNA Repair Enzymes / metabolism*
  • Electrophysiological Phenomena*
  • Female
  • Growth Hormone
  • Humans
  • Induced Pluripotent Stem Cells / physiology
  • Insulin-Like Growth Factor I
  • Male
  • Mutation*
  • Nerve Net / metabolism
  • Nerve Net / physiopathology*
  • Neurons / metabolism
  • Neurons / physiology*
  • Poly-ADP-Ribose Binding Proteins
  • Signal Transduction
  • Synapses / metabolism
  • Synapses / physiology


  • Poly-ADP-Ribose Binding Proteins
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • DNA Helicases
  • ERCC6 protein, human
  • DNA Repair Enzymes