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.

Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration

“…inj.) 3/3 3F/3F 4–7 months str TRAP of Aldh1L1-eGFP-L10a Microarray 10.17632/ktgcp4mtk2.1 [ 15 ] SOD1-G93A-1 Chronic G93A SOD1 vs wt 4/3 NA 90 days Spinal cord FACS Aldh1L1-eGFP/G93A SOD1 Microarray GSE111031 [ 16 ] SOD1-G93A-2 Chronic G93A SOD1 vs wt 3/3 3M/3M 120 days Spinal cord LCM of Aldh1L1+ cells Microarray GSE69166 [ 17 ] SOD1-G37R Chronic G37R SOD1 vs wt 4/6 4M/6M 8 months Spinal cord TRAP of Aldh1L1-eGFP-L10a RNA-seq GSE74724 [ 18 ] APPPS1-1 Chronic APPswePS1dE9 vs wt 4/4 NA 15–18 months Whole ctx FACS with Glt-1 Ab Microarray GSE74615 [ 19 ] APPPS1-2 Chronic APPswePS1dE9 vs wt 4/4 NA 15–18 months Whole ctx FACS of GFAP-GFP cells Microarray GSE74614 [ 20 ] APPPS1-3 Chronic APPswePS1dE9-GFP vs wt-GFP 4/7 4M/7M 9 months CA1 hipp FACS of eGFP+ cells RNA-seq GSE108520 [ 21 ] PS2APP-1 Chronic PS2APP vs wt 4/5 …”

“…Since the three acute MPTP time points are not independent datasets, only the 24 h dataset was used for the meta-analysis [15]. Mouse neurodegenerative datasets (n = 9) included ALS (various SOD1 mutants, n = 3) [16][17][18] and AD models of both brain β-amyloidosis (n = 5) (APPswe/PSEN1deltaE9 n = 3 and PS2APP n = 2) [19][20][21][22][23], and tauopathy (P301S-MAPT, n = 1) [23]. Whenever more than one age group was available, only the older age group was analyzed.…”

Deletion of the inflammatory S100-A9/MRP14 protein does not influence survival in hSOD1G93A ALS mice

“…Mean ages ± SEM of the different disease stages in our SOD1 G93A colony (S100a9+/+) defined by weight measurement were as follows: disease onset: 107. (Lobsiger et al, 2007;Miller et al, 2018;Zhang et al, 2014), S100a8 or S100a9 mRNA regulations measured by RT-qPCR performed in whole lumbar spinal cord tissues should represent microglial expression. RNA was extracted from whole lumbar mouse spinal cords and sciatic nerves (n=4 at every stage, except pre-symptomatic, n=5, end stage with n=6, and hSOD1 G93A :S100a9+/-, n=3 mice), using an OMNI international tissue master 125 tissue homogenizer in Qiazol reagent (Qiagen), using the Qiagen RNeasy mini lipid kit followed by a DNAse treatment (Qiagen).…”

Potential Roles of the WNT Signaling Pathway in Amyotrophic Lateral Sclerosis

“…Several of the most highly upregulated genes are related to the WNT pathway, especially the WNT/β–catenin pathway. Coiled–coil domain containing 85B was the gene most strongly upregulated; it is a nuclear transcriptional repressor and inhibits the function of β–catenin in a p53–dependent manner [ 63 ].…”