Aberrant Development Corrected in Adult-Onset Huntington's Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation.
Charlene Smith-Geater, Sarah J Hernandez, Ryan G Lim, Miriam Adam, Jie Wu, Jennifer T Stocksdale, Brook T Wassie, Maxwell Philip Gold, Keona Q Wang, Ricardo Miramontes, Lexi Kopan, Iliana Orellana, Shona Joy, Paul J Kemp, Nicholas D Allen, Ernest Fraenkel, Leslie M Thompson
Author Information
Charlene Smith-Geater: Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92697, USA.
Sarah J Hernandez: Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 96267, USA.
Ryan G Lim: Department of Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.
Miriam Adam: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Jie Wu: Department of Biological Chemistry, University of California Irvine, Irvine, CA 92617, USA.
Jennifer T Stocksdale: Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 96267, USA.
Brook T Wassie: LeadCrunch, San Diego, CA 92101, USA.
Maxwell Philip Gold: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Keona Q Wang: Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 96267, USA.
Ricardo Miramontes: Department of Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.
Lexi Kopan: Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 96267, USA.
Iliana Orellana: Department of Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA.
Shona Joy: Neural Stem Cell Institute, Rensselaer, NY 12144, USA.
Paul J Kemp: School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
Nicholas D Allen: School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK.
Ernest Fraenkel: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Leslie M Thompson: Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA 92697, USA; Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 96267, USA; Department of Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Department of Biological Chemistry, University of California Irvine, Irvine, CA 92617, USA. Electronic address: lmthomps@uci.edu.
Aberrant neuronal development and the persistence of mitotic cellular populations have been implicated in a multitude of neurological disorders, including Huntington's disease (HD). However, the mechanism underlying this potential pathology remains unclear. We used a modified protocol to differentiate induced pluripotent stem cells (iPSCs) from HD patients and unaffected controls into neuronal cultures enriched for medium spiny neurons, the cell type most affected in HD. We performed single-cell and bulk transcriptomic and epigenomic analyses and demonstrated that a persistent cyclin D1 neural stem cell (NSC) population is observed selectively in adult-onset HD iPSCs during differentiation. Treatment with a WNT inhibitor abrogates this NSC population while preserving neurons. Taken together, our findings identify a mechanism that may promote aberrant neurodevelopment and adult neurogenesis in adult-onset HD striatal neurons with the potential for therapeutic compensation.
