Progerin-Induced Transcriptional Changes in Huntington’s Disease Human Pluripotent Stem Cell-Derived Neurons


Huntington’s disease (HD) is a neurodegenerative late-onset genetic disorder caused by CAG expansions in the coding region of the Huntingtin (HTT) gene, resulting in a poly-glutamine (polyQ) expanded HTT protein. Considerable efforts have been devoted for studying HD and other polyQ diseases using animal models and cell culture systems, but no treatment currently exists. Human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) offer an elegant solution for modeling human diseases. However, as embryonic or rejuvenated cells, respectively, these pluripotent stem cells (PSCs) do not recapitulate the late-onset feature of the disease. Here, we applied a robust and rapid differentiation protocol to derive electrophysiologically active striatal GABAergic neurons from human wild-type (WT) and HD ESCs and iPSCs. RNA-seq analyses revealed that HD and WT PSC-derived neurons are highly similar in their gene expression patterns. Interestingly, ectopic expression of Progerin in both WT and HD neurons exacerbated the otherwise non-significant changes in gene expression between these cells, revealing IGF1 and genes involved in neurogenesis and nervous system development as consistently altered in the HD cells. This work provides a useful tool for modeling HD in human PSCs and reveals potential molecular targets altered in HD neurons.

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Data Availability

All data are available at through GEO (GSE111622).


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Author information

D. Cohen-Carmon, M. Sorek, V. Lerner, Y. Yarom, and E. Meshorer designed the research; D. Cohen-Carmon, M. Sorek, V. Lerner, and M. Nissim-Rafinia performed the research; D. Cohen-Carmon, M. Sorek, and V. Lerner analyzed the data; Cohen-Carmon, M. Sorek, and E. Meshorer wrote the paper.

Correspondence to Eran Meshorer.

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The original version of this article was revised: An author named Mundackal S. Divya has been added.

Dorit Cohen-Carmon and Matan Sorek contributed equally to this work.

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Cohen-Carmon, D., Sorek, M., Lerner, V. et al. Progerin-Induced Transcriptional Changes in Huntington’s Disease Human Pluripotent Stem Cell-Derived Neurons. Mol Neurobiol (2019) doi:10.1007/s12035-019-01839-8

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  • Progerin
  • iPS cells
  • iPSC
  • Neuronal differentiation
  • Embryonic stem cells
  • HD