Faulty neuronal determination and cell polarization are reverted by modulating HD early phenotypes

Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E762-E771. doi: 10.1073/pnas.1715865115. Epub 2018 Jan 8.


Increasing evidence suggests that early neurodevelopmental defects in Huntington's disease (HD) patients could contribute to the later adult neurodegenerative phenotype. Here, by using HD-derived induced pluripotent stem cell lines, we report that early telencephalic induction and late neural identity are affected in cortical and striatal populations. We show that a large CAG expansion causes complete failure of the neuro-ectodermal acquisition, while cells carrying shorter CAGs repeats show gross abnormalities in neural rosette formation as well as disrupted cytoarchitecture in cortical organoids. Gene-expression analysis showed that control organoid overlapped with mature human fetal cortical areas, while HD organoids correlated with the immature ventricular zone/subventricular zone. We also report that defects in neuroectoderm and rosette formation could be rescued by molecular and pharmacological approaches leading to a recovery of striatal identity. These results show that mutant huntingtin precludes normal neuronal fate acquisition and highlights a possible connection between mutant huntingtin and abnormal neural development in HD.

Keywords: Huntington’s disease; human iPS lines; neurodevelopment; organoids; striatal differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Polarity
  • Humans
  • Huntington Disease / genetics
  • Huntington Disease / physiopathology*
  • Induced Pluripotent Stem Cells
  • Neurogenesis*
  • Telencephalon / cytology