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

Molecular Neurobiology volume 57, pages 1768–1777 (2020)Cite this article

A Correction to this article was published on 15 January 2020

This article has been updated

Abstract

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).

Change history

  • 15 January 2020

    In the original version of the paper, the name of one of the contributing authors, Dr. Mundackal S. Divya (orcid:0000-0002-2869-7191).

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Funding

The work was supported by the Israel Science Foundation (1140/17 to E.M.), a TEVA National Network of Excellence award (to E.M. and D.C.C), and the Azrieli Foundation Fellowship (to M.S.).

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Authors and Affiliations

  1. Department of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel

    Dorit Cohen-Carmon, Matan Sorek, Mundackal S. Divya, Malka Nissim-Rafinia & Eran Meshorer

  2. The Edmond and Lily Safra Center for Brain Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel

    Matan Sorek, Vitaly Lerner, Yosef Yarom & Eran Meshorer

  3. Department of Neurobiology, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel

    Vitaly Lerner & Yosef Yarom

  4. Department of Pathology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, 695011, Kerala, India

    Mundackal S. Divya

Authors
  1. Dorit Cohen-Carmon
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  2. Matan Sorek
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  4. Mundackal S. Divya
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  5. Malka Nissim-Rafinia
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Contributions

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.

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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 57, 1768–1777 (2020). https://doi.org/10.1007/s12035-019-01839-8

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