Insights into the Pathobiology of GM1 Gangliosidosis from Single-Nucleus Transcriptomic Analysis of CNS Cells in a Mouse Model
<p>Construction of a single-cell transcriptomic atlas of brain tissue in GM1 mice. (<b>A</b>) Single-nucleus RNA sequencing (snRNA-seq) profiling workflow. (<b>B</b>) A dot plot demonstrating the classical marker genes used for the identification of a cluster cell type. The dot size reflects the percentage and the color intensity is proportional to the average expression. (<b>C</b>) A Uniform Manifold Approximation and Projection (UMAP) plot showing the six major cell types across the brain tissues, based on data from snRNA-seq. (<b>D</b>) The proportions of the main cell types in both GM1 and WT brains.</p> "> Figure 2
<p>GM1-related changes in gene expression. (<b>A</b>) A volcano plot showing –log10 (false discovery rate [FDR]) and logFoldChange (FC) values for the differentially expressed genes (DEGs) of the six cell types. (<b>B</b>) A histogram of the Gene Set Enrichment Analysis (GSEA-based pathway enrichment) for the DEGs identified in the major cell types.</p> "> Figure 2 Cont.
<p>GM1-related changes in gene expression. (<b>A</b>) A volcano plot showing –log10 (false discovery rate [FDR]) and logFoldChange (FC) values for the differentially expressed genes (DEGs) of the six cell types. (<b>B</b>) A histogram of the Gene Set Enrichment Analysis (GSEA-based pathway enrichment) for the DEGs identified in the major cell types.</p> "> Figure 3
<p>Transcriptional changes in neurons of GM1 gangliosidosis model mice. (<b>A</b>) A dot plot showing Gene Ontology (GO) term enrichment based on the differentially expressed genes (DEGs) identified in neurons. (<b>B</b>) A UMAP plot showing the NEU subclusters. (<b>C</b>) A violin plot showing the expression of marker genes (excitatory neurons [ExNs]: <span class="html-italic">Slc17a7</span>, <span class="html-italic">Slc17a6</span>; inhibitory neurons [InNs]: <span class="html-italic">Gad1</span>, <span class="html-italic">Gad2</span>) in neuronal subclusters. (<b>D</b>) The proportions of the neuronal subclusters in the brains of GM1 and wild-type (WT) mice. (<b>E</b>) A dot plot showing GO term enrichment based on the DEGs identified in subcluster 9.</p> "> Figure 4
<p>Transcriptional changes in microglia (MG) in GM1 gangliosidosis model mice. (<b>A</b>) A dot plot showing GO term enrichment based on the differentially expressed genes (DEGs) identified in microglia. (<b>B</b>) UMAP plot showing the MG subclusters. (<b>C</b>) The proportions of cells of the MG subclusters in the brains of GM1 and wild-type mice. (<b>D</b>) A UMAP plots showing the expression of marker genes in the MG subclusters. (<b>E</b>) A dot plot showing GO term enrichment based on the DEGs identified in the MG subclusters.</p> "> Figure 5
<p>Transcriptional changes in astrocytes (ASCs) in GM1 gangliosidosis model mice. (<b>A</b>) A dot plot showing Gene Ontology (GO) term enrichment based on the differentially expressed genes (DEGs) identified in ASCs. (<b>B</b>) A UMAP plot showing the ASC subclusters. (<b>C</b>) The proportions of the ASC subclusters in the brains of GM1 and wild-type mice. (<b>D</b>) A UMAP plots showing the expression of marker genes in the ASC subclusters. (<b>E</b>) Pseudo-time showing the relative positioning of ASCs along the trajectory. (<b>F</b>) A dot plot showing GO term enrichment based on the DEGs identified in the ASC0 subcluster.</p> "> Figure 6
<p>Transcriptional changes in oligodendroglial lineage cells in GM1 gangliosidosis model mice. (<b>A</b>) A dot plot showing Gene Ontology (GO) term enrichment based on the differentially expressed genes (DEGs) identified in oligodendrocytes (OLGs). (<b>B</b>) A dot plot showing GO term enrichment based on the DEGs identified in oligodendrocyte progenitor cells (OPCs). (<b>C</b>) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with the DEGs in OLGs. (<b>D</b>) KEGG pathways associated with the DEGs in the OPCs.</p> "> Figure 6 Cont.
<p>Transcriptional changes in oligodendroglial lineage cells in GM1 gangliosidosis model mice. (<b>A</b>) A dot plot showing Gene Ontology (GO) term enrichment based on the differentially expressed genes (DEGs) identified in oligodendrocytes (OLGs). (<b>B</b>) A dot plot showing GO term enrichment based on the DEGs identified in oligodendrocyte progenitor cells (OPCs). (<b>C</b>) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with the DEGs in OLGs. (<b>D</b>) KEGG pathways associated with the DEGs in the OPCs.</p> "> Figure 7
<p>Changes in intercellular communication in GM1 gangliosidosis model mice. (<b>A</b>) The number and strength of ligand–receptor interactions in the GM1 and wild-type (WT) groups. (<b>B</b>) Heatmaps of the interactions change between GM1 and WT groups. (<b>C</b>) Heatmaps of the incoming signaling patterns in the GM1 and WT groups.</p> ">
Abstract
:1. Introduction
2. Results
2.1. Single-Nucleus Transcriptome Profiling Identified Cell Populations in the Brains of GM1 Gangliosidosis Mice
2.2. Differential Gene Expression and Functional Analyses Highlighted Abnormal Expression Patterns in Various Cell Types in GM1 Mice
2.3. Altered Gene Expression in Neurons of GM1 Mice Induces Neurodegeneration-Related Changes
2.4. Microglia Exert Anti-Inflammatory Functions and Are Involved in the Regulation of Neuronal Death Signaling Pathways in GM1 Mice
2.5. Astrocytes Were Not Activated and Disrupted Synaptic Function Regulation in GM1 Mice
2.6. OLGs and OPCs Displayed Distinct Responses in GM1 Mice
2.7. Changes in Intercellular Communication in the CNS Revealed the Microenvironment in the GM1 Mouse Brain
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. Single-Nucleus RNA Sequencing
4.3. Data Processing and Quality Control
4.4. Clustering and Cell Type Identification
4.5. Differential Gene Expression and Pathway Analysis
4.6. Cell–Cell Communication Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Liu, S.; Xie, T.; Huang, Y. Insights into the Pathobiology of GM1 Gangliosidosis from Single-Nucleus Transcriptomic Analysis of CNS Cells in a Mouse Model. Int. J. Mol. Sci. 2024, 25, 9712. https://doi.org/10.3390/ijms25179712
Liu S, Xie T, Huang Y. Insights into the Pathobiology of GM1 Gangliosidosis from Single-Nucleus Transcriptomic Analysis of CNS Cells in a Mouse Model. International Journal of Molecular Sciences. 2024; 25(17):9712. https://doi.org/10.3390/ijms25179712
Chicago/Turabian StyleLiu, Sichi, Ting Xie, and Yonglan Huang. 2024. "Insights into the Pathobiology of GM1 Gangliosidosis from Single-Nucleus Transcriptomic Analysis of CNS Cells in a Mouse Model" International Journal of Molecular Sciences 25, no. 17: 9712. https://doi.org/10.3390/ijms25179712