Intersecting impact of CAG repeat and huntingtin knockout in stem cell-derived cortical neurons
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
- Matthew Leventhal (ORCID: https://orcid.org/0000-0002-5995-5202)
- Jennifer E. Van Eyk (ORCID: https://orcid.org/0000-0001-9050-148X)
- Kanchan Sarda
- Terry T.‐K. Huang (ORCID: https://orcid.org/0000-0001-5544-5187)
- Dan P. Felsenfeld (ORCID: https://orcid.org/0000-0003-4044-459X)
- Niveda Sundararaman (ORCID: https://orcid.org/0000-0001-7708-3754)
- Yuxin Xu (ORCID: https://orcid.org/0000-0002-0200-4633)
- Heather Johnson (ORCID: https://orcid.org/0000-0001-7468-0705)
- Jennifer T. Stocksdale (ORCID: https://orcid.org/0000-0002-4304-6266)
- Zohreh Faghihmonzavi
- Leslie Michels Thompson (ORCID: https://orcid.org/0000-0003-4573-9514)
- Ernest Fraenkel (ORCID: https://orcid.org/0000-0001-9249-8181)
- Jie Wu (ORCID: https://orcid.org/0000-0003-2759-5879)
- Ricardo Miramontes (ORCID: https://orcid.org/0000-0002-9231-2479)
- Keona Q. Wang (ORCID: https://orcid.org/0000-0002-7715-2489)
- Steven M. Finkbeiner (ORCID: https://orcid.org/0000-0002-3480-394X)
- Stephanie Lam
- Rogelio Tomás (ORCID: https://orcid.org/0000-0002-9857-1703)
- Julia Kaye (ORCID: https://orcid.org/0000-0001-7442-0882)
- Michael E. Foster (ORCID: https://orcid.org/0000-0002-4164-3526)
- Min‐Gyoung Shin (ORCID: https://orcid.org/0000-0001-8350-1334)
- Vineet Vaibhav
- Yi Wang (ORCID: https://orcid.org/0000-0001-6082-8721)
- Thomas Vogt (ORCID: https://orcid.org/0000-0001-6155-3360)
- Charlene Smith
- Mariya Barch
- Naufa Armani
- Chris Paiz
- Lindsay Easter
- Erse Duderstadt
- Yogi Raghav
Institutions
- Cedars-Sinai Medical Center (US)
- Gladstone Institutes (US)
- University of California, Irvine (US)
- Cedars-Sinai Smidt Heart Institute (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Neurobiology of Disease
- Published
- 2025-04-19
- DOI
- https://doi.org/10.1016/j.nbd.2025.106914
- Citations
- 4
- Primary Topic
- Genetic Neurodegenerative Diseases
- Type
- article
- Field-Weighted Citation Impact
- 3.64