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

doi:10.1016/j.isci.2022.105732

Single-nuclei transcriptome analysis of Huntington disease iPSC and mouse astrocytes implicates maturation and functional deficits

iScience. 2022 Dec 6;26(1):105732. doi: 10.1016/j.isci.2022.105732. eCollection 2023 Jan 20.

Authors

Andrea M Reyes-Ortiz¹, Edsel M Abud², Mara S Burns², Jie Wu¹, Sarah J Hernandez², Nicolette McClure³, Keona Q Wang², Corey J Schulz³, Ricardo Miramontes⁴, Alice Lau⁵, Neethu Michael², Emily Miyoshi², David Van Vactor⁶, John C Reidling⁴, Mathew Blurton-Jones^{2

3

4}, Vivek Swarup^{2

4}, Wayne W Poon⁴, Ryan G Lim⁴, Leslie M Thompson^{1

2

3

5

4}

Affiliations

¹ Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92617, USA.
² Department of Neurobiology & Behavior, University of California, Irvine, Irvine, CA 92617, USA.
³ Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92617, USA.
⁴ Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92617, USA.
⁵ Department of Psychiatry & Human Behavior, University of California, Irvine, Irvine, CA 92617, USA.
⁶ Harvard Medical School, Department of Cell Biology, Boston, MA 02115, USA.

Abstract

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.

Keywords: Neurology; Omics.

Abstract

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