Single-nuclei Transcriptome Analysis of Huntington Disease IPSC and Mouse Astrocytes Implicates Maturation and Functional Deficits

Overview

Journal iScience

Publisher Cell Press

Date 2023 Jan 2

PMID 36590162

Authors

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

Soon will be listed here.

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.

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