Intersecting impact of CAG repeat and huntingtin knockout in stem cell-derived cortical neurons.

Journal: Neurobiology of disease
Published Date: Apr 19, 2025

Abstract

Huntington's Disease (HD) is caused by a CAG repeat expansion in the gene encoding huntingtin (HTT). While normal HTT function appears impacted by the mutation, the specific pathways unique to CAG repeat expansion versus loss of normal function are unclear. To understand the impact of the CAG repeat expansion, we evaluated biological signatures of HTT knockout (HTT KO) versus those that occur from the CAG repeat expansion by applying multi-omics, live cell imaging, survival analysis and a novel feature-based pipeline to study cortical neurons (eCNs) derived from an isogenic human embryonic stem cell series (RUES2). HTT KO and the CAG repeat expansion influence developmental trajectories of eCNs, with opposing effects on growth. Network analyses of differentially expressed genes and proteins associated with enriched epigenetic motifs identified subnetworks common to CAG repeat expansion and HTT KO that include neuronal differentiation, cell cycle regulation, and mechanisms related to transcriptional repression, and may represent gain-of-function mechanisms that cannot be explained by HTT loss of function alone. A combination of dominant and loss-of-function mechanisms are likely involved in the aberrant neurodevelopmental and neurodegenerative features of HD that can help inform therapeutic strategies.

Authors

  • Jennifer T Stocksdale
    Department of Neurobiology and Behavior, UC Irvine, Irvine, CA 92677, USA.
  • Matthew J Leventhal
    MIT PhD Program in Computational and Systems Biology, Cambridge, MA 02139, USA; MIT Department of Biological Engineering, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Stephanie Lam
    Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Yu-Xin Xu
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Yang Oliver Wang
    Advanced Clinical Biosystems Research Institute, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Keona Q Wang
    Department of Neurobiology and Behavior, UC Irvine, Irvine, CA 92677, USA.
  • Reuben Thomas
    Gladstone Institute of Data Science and Biotechnology, San Francisco, CA 94158, USA.
  • Zohreh Faghihmonzavi
    Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Yogindra Raghav
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Charlene Smith
    Department of Psychiatry and Human Behavior, UC Irvine, Irvine, CA 92697, USA.
  • Jie Wu
    Center of Disease Control of Qingdao, 175 Shandong Road, Qingdao, Shandong, 266001, China.
  • Ricardo Miramontes
    Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA 92697, USA.
  • Kanchan Sarda
    Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Heather Johnston
    Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Min-Gyoung Shin
    University of Southern California, 1050 Childs Way (USC), Los Angeles, CA, 90089-0371, USA.
  • Terry Huang
    Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Mikelle Foster
    Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Mariya Barch
    Taube/Koret Center for Neurodegenerative Disease Research and DaedalusBio, Gladstone, USA.
  • Naufa Amirani
    Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Chris Paiz
    Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Lindsay Easter
    Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Erse Duderstadt
    Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Vineet Vaibhav
    Advanced Clinical Biosystems Research Institute, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Niveda Sundararaman
    Advanced Clinical Biosystems Research Institute, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Dan P Felsenfeld
    CHDI Management, Inc, New York, NY 10001, USA.
  • Thomas F Vogt
    CHDI Management, Inc, New York, NY 10001, USA.
  • Jennifer Van Eyk
    Advanced Clinical Biosystems Research Institute, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • Steve Finkbeiner
    Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA; Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurology, University of California San Francisco, San Francisco, CA 94158, USA; Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Julia A Kaye
    Center for Systems and Therapeutics, Gladstone Institutes, San Francisco, CA 94158, USA; Taube/Koret Center for Neurodegenerative Disease Research, Gladstone Institutes, San Francisco, CA 94158, USA.
  • Ernest Fraenkel
    Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Leslie M Thompson
    Department of Neurobiology and Behavior, UC Irvine, Irvine, CA 92677, USA; Department of Psychiatry and Human Behavior, UC Irvine, Irvine, CA 92697, USA; Department of Biological Chemistry, UC Irvine, Irvine, CA 92697, USA; Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA 92697, USA. Electronic address: lmthomps@uci.edu.

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