Spatial and Temporal Diversity of Astrocyte Phenotypes in Spinocerebellar Ataxia Type 1 Mice

Juao-Guilherme Rosa, Katherine A Hamel, Carrie A Sheeler, Ella Borgenheimer, Stephen Gilliat, Alyssa Soles, Ferris J. Ghannoum, Kaelin Sbrocco, Hillary Handler, Orion Rainwater, Ryan Kang, Marija Cvetanovic

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

While astrocyte heterogeneity is an important feature of the healthy brain, less is understood about spatiotemporal heterogeneity of astrocytes in brain disease. Spinocerebellar ataxia type 1 (SCA1) is a progressive neurodegenerative disease caused by a CAG repeat expansion in the gene Ataxin1 (ATXN1). We characterized astrocytes across disease progression in the four clinically relevant brain regions, cerebellum, brainstem, hippocampus, and motor cortex, of Atxn1154Q/2Q mice, a knock-in mouse model of SCA1. We found brain region-specific changes in astrocyte density and GFAP expression and area, early in the disease and prior to neuronal loss. Expression of astrocytic core homeostatic genes was also altered in a brain region-specific manner and correlated with neuronal activity, indicating that astrocytes may compensate or exacerbate neuronal dysfunction. Late in disease, expression of astrocytic homeostatic genes was reduced in all four brain regions, indicating loss of astrocyte functions. We observed no obvious correlation between spatiotemporal changes in microglia and spatiotemporal astrocyte alterations, indicating a complex orchestration of glial phenotypes in disease. These results support spatiotemporal diversity of glial phenotypes as an important feature of the brain disease that may contribute to SCA1 pathogenesis in a brain region and disease stage-specific manner.

Original languageEnglish (US)
Article number3323
JournalCells
Volume11
Issue number20
DOIs
StatePublished - Oct 2022

Bibliographical note

Funding Information:
This work was supported by National Institute of Health NINDS awards (R01 NS197387 and R01 NS109077 to M.C.).

Publisher Copyright:
© 2022 by the authors.

Keywords

  • SCA1
  • astrocytes
  • brain region
  • gene expression
  • microglia
  • morphology
  • neurodegeneration

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