Cortical astroglia undergo transcriptomic dysregulation in the G93A SOD1 ALS mouse model

Abstract

Astroglia are the most abundant glia cell in the central nervous system, playing essential roles in maintaining homeostasis. Key functions of astroglia include, but are not limited to, neurotransmitter recycling, ion buffering, immune modulation, neurotrophin secretion, neuronal synaptogenesis and elimination, and blood–brain barrier maintenance. In neurological diseases, it is well appreciated that astroglia play crucial roles in the disease pathogenesis. In amyotrophic lateral sclerosis (ALS), a motor neuron degenerative disease, astroglia in the spinal cord and cortex downregulate essential transporters, among other proteins, that exacerbate disease progression. Spinal cord astroglia undergo dramatic transcriptome dysregulation. However, in the cortex, it has not been well studied what effects glia, especially astroglia, have on upper motor neurons in the pathology of ALS. To begin to shed light on the involvement and dysregulation that astroglia undergo in ALS, we isolated pure grey-matter cortical astroglia and subjected them to microarray analysis. We uncovered a vast number of genes that show dysregulation at end-stage in the ALS mouse model, G93A SOD1. Many of these genes play essential roles in ion homeostasis and the Wnt-signaling pathway. Several of these dysregulated genes are common in ALS spinal cord astroglia, while many of them are unique. This database serves as an approach for understanding the significance of dysfunctional genes and pathways in cortical astroglia in the context of motor neuron disease, as well as determining regional astroglia heterogeneity, and providing insight into ALS pathogenesis.

Keywords:

• ALS
• SOD1
• astroglia
• transcriptome
• neurodegeneration

Acknowledgments

The authors would like to thank the Johns Hopkins Microarray and Bioinformatics core for their assistance and knowledge, in particular, Connie Talbot for his guidance on the bioinformatic analyses, and the Johns Hopkins University School of Public Health FACS Center.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This research was supported by the National Science Foundation Graduate Research Fellowship Program (S. J. M.), and the National Institutes of Health NS085207 and NS092067, Muscular Dystrophy Association, Target ALS, and the ALS Association (J. D. R.), and National Institute of Neurological Disorders and Stroke.