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. 2022 Mar 15:15:825031.
doi: 10.3389/fnmol.2022.825031. eCollection 2022.

Key Disease Mechanisms Linked to Amyotrophic Lateral Sclerosis in Spinal Cord Motor Neurons

Virginie Bottero  1 , Jose A Santiago  2 , James P Quinn  3 , Judith A Potashkin  1
Affiliations

Key Disease Mechanisms Linked to Amyotrophic Lateral Sclerosis in Spinal Cord Motor Neurons

Virginie Bottero et al. Front Mol Neurosci. .

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no modifying treatments available. The molecular mechanisms underpinning disease pathogenesis are not fully understood. Recent studies have employed co-expression networks to identify key genes, known as "switch genes", responsible for dramatic transcriptional changes in the blood of ALS patients. In this study, we directly investigate the root cause of ALS by examining the changes in gene expression in motor neurons that degenerate in patients. Co-expression networks identified in ALS patients' spinal cord motor neurons revealed 610 switch genes in seven independent microarrays. Switch genes were enriched in several pathways, including viral carcinogenesis, PI3K-Akt, focal adhesion, proteoglycans in cancer, colorectal cancer, and thyroid hormone signaling. Transcription factors ELK1 and GATA2 were identified as key master regulators of the switch genes. Protein-chemical network analysis identified valproic acid, cyclosporine, estradiol, acetaminophen, quercetin, and carbamazepine as potential therapeutics for ALS. Furthermore, the chemical analysis identified metals and organic compounds including, arsenic, copper, nickel, and benzo(a)pyrene as possible mediators of neurodegeneration. The identification of switch genes provides insights into previously unknown biological pathways associated with ALS.

Keywords: ALS; amyotrophic lateral sclerosis; co-expression networks; motor neuron disease; network analysis; neurodegeneration; switch genes.

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Conflict of interest statement

JS is the founder of and employed by NeuroHub Analytics, LLC. JQ is the founder of and employed by Q Regulating Systems, LLC. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overall study design. ArrayExpress and NCBI GEO databases were searched for human transcriptomic studies in ALS. SWIM analysis was performed to identify switch genes, which were further analyzed for functional pathways, regulatory transcription factors, miRNAs, and chemical associations using NetworkAnalyst.
Figure 2
Figure 2
The panels (A–F) represent the results for GSE833, GSE19332, GSE20589, GSE26927, GSE56500, and GSE68605, respectively. Distribution of log2 fold change values where the red bars are selected for further analysis. The x-axis represents the fold-change value (log2 of the fold-change) that is the ratio of the average expression data in ALS patients compared to the average expression data in normal controls computed for protein-coding and non-coding RNAs. The y-axis represents the frequency of the obtained fold-change values. The gray bars represent the fold-change values associated with protein-coding and non-coding RNAs that will be discarded according to the selected threshold. The red bars represent the fold-change values associated with protein-coding and non-coding RNAs that were retained for further analysis.
Figure 3
Figure 3
GSE52946 SWIM analysis. (A) Distribution of log2 fold change values where the red bars are selected for further analysis. (B) Heat cartography maps of nodes of the ALS/healthy correlation. (C) Dendrogram and heat map for switch genes. The suffix D indicates the samples from the ALS cohort. The colors represent expression levels, with blue indicating downregulated and yellow indicating upregulated. (D) Robustness of the correlation network.
Figure 4
Figure 4
The panels (A–F) represent the results for GSE833, GSE19332, GSE20589, GSE26927, GSE56500, and GSE68605, respectively. Heat cartography map with nodes colored by their average Pearson Correlation Coefficient (APCC) value. Yellow nodes are party and date hubs, which are positively correlated in expression with their interaction partners. Blue nodes are the fight-club hubs, with an average negative correlation in expression with their interaction partners. Blue nodes falling in the region R4 are the switch genes characterized by low Zg and high Kπ values and are connected mainly outside their module. Thus, region R4 represents the switch genes.
Figure 5
Figure 5
The panels (A–F) represent the results for GSE833, GSE19332, GSE20589, GSE26927, GSE56500, and GSE68605, respectively. Dendrogram and heat map analysis for switch genes. The colors represent different expression levels that increase from blue to yellow. The samples marked with a D after the number are the ones from the diseased cohort. The red, pink, and white bar at the top is an alternate marker of the cohorts. When the sample size is large the x-axis, labels are disabled. Red and pink denote ALS samples.
Figure 6
Figure 6
The panels (A–F) represent the results for GSE833, GSE19332, GSE20589, GSE26927, GSE56500, and GSE68605, respectively. Robustness of the correlation network. The x-axis represents the cumulative fraction of removed nodes, while the y-axis represents the average shortest path. The shortest path between two nodes is the minimum number of consecutive edges connecting them. Thus, each curve corresponds to the variation of the average shortest path of the correlation network as a function of the removal of nodes specified by the colors of each curve.
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