Single-nuclei transcriptome analysis of Huntington disease iPSC and mouse astrocytes implicates maturation and functional deficits
Andrea M. Reyes-Ortiz,
Edsel M. Abud,
Mara S. Burns,
Jie Wu,
Sarah J. Hernandez,
Nicolette McClure,
Keona Q. Wang,
Corey J. Schulz,
Ricardo Miramontes,
Alice Lau,
Neethu Michael,
Emily Miyoshi,
David Van Vactor,
John C. Reidling,
Mathew Blurton-Jones,
Vivek Swarup,
Wayne W. Poon,
Ryan G. Lim,
Leslie M. Thompson
Affiliations
Andrea M. Reyes-Ortiz
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA
Edsel M. Abud
Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA
Mara S. Burns
Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA
Jie Wu
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA
Sarah J. Hernandez
Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA
Nicolette McClure
Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA
Keona Q. Wang
Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA
Corey J. Schulz
Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA
Ricardo Miramontes
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA
Alice Lau
Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA 92617, USA
Neethu Michael
Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA
Emily Miyoshi
Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA
David Van Vactor
Harvard Medical School, Department of Cell Biology, Boston, MA 02115, USA
John C. Reidling
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA
Mathew Blurton-Jones
Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA
Vivek Swarup
Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA
Wayne W. Poon
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA
Ryan G. Lim
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA
Leslie M. Thompson
Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA; Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA; Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA; Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA 92617, USA; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA; Corresponding author
Summary: Huntington disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene that alters cellular homeostasis, particularly in the striatum and cortex. Astrocyte signaling that establishes and maintains neuronal functions are often altered under pathological conditions. We performed single-nuclei RNA-sequencing on human HD patient-induced pluripotent stem cell (iPSC)-derived astrocytes and on striatal and cortical tissue from R6/2 HD mice to investigate high-resolution HD astrocyte cell state transitions. We observed altered maturation and glutamate signaling in HD human and mouse astrocytes. Human HD astrocytes also showed upregulated actin-mediated signaling, suggesting that some states may be cell-autonomous and human specific. In both species, astrogliogenesis transcription factors may drive HD astrocyte maturation deficits, which are supported by rescued climbing deficits in HD drosophila with NFIA knockdown. Thus, dysregulated HD astrocyte states may induce dysfunctional astrocytic properties, in part due to maturation deficits influenced by astrogliogenesis transcription factor dysregulation.
