Dynamic astrocytic gene expression profiles after ischemic stroke
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE238125 | GEO | 2024/05/23
REPOSITORIES: GEO
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Project description:Analysis of microglial gene expression profiles after ischemic stroke. Stroke is a complicated disease caused by the interaction of multiple celltypes. Results provide new insights into the molecular mechanisms underlying microglial activation after ischemic stroke.
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Project description:Dynamic astrocytic gene expression profiles after ischemic stroke
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Project description:Roles of reactive perivascular astrocytes in dysregulation of the blood-brain barrier (BBB) function and cerebral perfusion are not well defined. Here, we investigated transformation of reactive astrocyte function for vascular repair after ischemic stroke by targeted deletion of astrocytic Na+/H+ exchanger isoform 1 in Gfap-CreERT2+/-;Nhe1f/f (Nhe1 Astro-KO) mice. Control Gfap-CreERT2+/-;Nhe1f/f (wild-type) mice displayed BBB damage (elevated endothelial transcytosis and intracellular vesicles) and persistent cerebral hypoperfusion in an ischemic stroke model (transient middle cerebral artery occlusion). In contrast, Nhe1 Astro-KO mice exhibited significantly less endothelial transcytosis and vesicle formation, and increased angiogenesis and cerebral blood perfusion (CBF) post-stroke. Bulk RNA-sequencing transcriptome analysis of isolated GFAP+ reactive astrocytes from wild-type and Nhe1 Astro-KO ischemic brains revealed that ~177 genes were differentially upregulated, with the Wnt7a mRNA among the top upregulated genes, along with additional Wnt pathway genes (Wnt7b, Fzd9, Fzd10, and Ndp). Abundant Wnt7a/b and β-catenin protein expression was detected in cerebral vessels of Nhe1 Astro-KO ischemic brains but not in the wild-type brains. Selective activation of Wnt/β-catenin pathway in cerebral vessels of Nhe1 Astro-KO ischemic brains was further validated using the Wnt reporter line TCF/LEF::H2B-eGFP; Gfap-CreERT2+/-;Nhe1f/f mice. Lastly, the role of Wnt/β-catenin pathway in resistance of Nhe1 Astro-KO mice to stroke-mediated BBB damage was tested by administration of Wnt/β-catenin inhibitor XAV-939. Taken together, we report that transforming reactive astrocyte function by upregulating astrocytic Wnt/β-catenin signaling activity is a novel mechanism to reduce the BBB endothelial damage, stimulate vascular repair, and restore cerebral blood flow after ischemic stroke.
2020-12-08 | GSE145839 | GEO
Project description:Ischemic stroke induces pathological glycogen deposition in astrocytes, but its role in post-injury neural dysfunction remains undefined. We reveal that glycogen-laden astrocytes in the ischemic penumbra undergo HDAC3-dependent mitochondrial fragmentation via a stress granule-mediated mechanism, exacerbating neuronal injury and hindering functional recovery. Mechanistic studies demonstrate that glycogen aggregates sequester cytoplasmic HDAC3, enabling its translocation to mitochondria. There, HDAC3 deacetylates outer mitochondrial membrane protein ATAD3A, promoting oligomerization-driven mitochondrial fission. Astrocyte-specific ATAD3A ablation prevents stroke-induced synaptic disorganization, neural circuit disruption, and cognitive deficits. Therapeutically, combined administration of cotadutide (a glycogen-depleting GLP-1/GCGR agonist) and HDAC3 inhibitor RGFP966 reverses glycogen accumulation, rescues mitochondrial architecture/function, and restores synaptic plasticity and circuit reorganization, thereby accelerating sensorimotor recovery. Our work identifies glycogen stress granules as pathogenic signaling hubs linking astrocytic metabolic stress to mitochondrial failure through compartmentalized HDAC3-ATAD3A crosstalk, and proposes a dual-target paradigm addressing both substrate overload and protein acetylation dynamics for stroke neurorestoration.
2025-05-10 | GSE295882 | GEO
Project description:Dynamic microglial gene expression profiles after ischemic stroke
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Project description:Cluster analysis using nonlinear dimensionality reduction ([tSNE]) revealed the differences in global gene expression profiles of healthy and injured striatum, and identified clusters of cells with unique genetic signatures in both ischemic brain and hemorrhagic brain. Genes with p-value < 0.05 and fold change ≥1.5 were regarded as differentially expressed genes (DEGs). For astrocytes, 135 DEGs were downregulated in hemorrhagic stroke compared to ischemic stroke. The secondary profiling of astrocytic subtypes yielded 10 different subtypes with distinct functional cell identities. For microglia, tSNE map indicated the distribution and proportion of microglia/macrophage were very similar in in the ischemic and hemorrhagic stroke models. We obtained 75 DEGs in total (hemorrhagic stroke vs. ischemic stroke, 54 were upregulated, 21 were downregulated) .
2021-10-31 | GSE167593 | GEO
Project description:The purpose of this project was to elucidate gene expression in the peripheral whole blood of acute ischemic stroke patients to identify a panel of genes for the diagnosis of acute ischemic stroke. Peripheral blood samples were collected in Paxgene Blood RNA tubes from stroke patients who were >18 years of age with MRI diagnosed ischemic stroke and controls who were non-stroke neurologically healthy. The results suggest a panel of genes can be used to diagnose ischemic stroke, and provide information about the biological pathways involved in the response to acute ischemic stroke in humans. Total RNA extracted from whole blood in n=39 ischemic stroke patients compared to n=24 healthy control subjects.
2010-06-08 | E-GEOD-16561 | biostudies-arrayexpress
Project description:Ischemic stroke induces pathological glycogen deposition in astrocytes, but its role in post-injury neural dysfunction remains undefined. We firstly intend to identify the glycogen granule proteome after ischemic stroke via glycogen pulldown for protein mass spectrometry detection. KEGG pathway analysis of the glycogen granule proteome revealed highly enriched mitochondrial-related functional signals, such as respiratory chain complexes, mitochondrial respirasomes, and mitochondrial membrane protein complexes. GO functional annotation of biological processes revealed enrichment of genes related to mitochondrial electron transport, respiratory chain complexes, and mitochondrial ATP synthesis. To explore detailed mitochondrial biological processes in detail, we summarized mitochondrial function gene sets from the mitoproteome database and intersected them with many glycogen-enriched proteins. The data revealed that glycogen stress granules are related mainly to oxidative phosphorylation subunits, assembly factors and electron carriers; mitochondrial dynamics (such as MFF, DNM1L, and GDAP1), homeostasis, and quality control (such as AFG3L2, CLPB, and ATAD3A). Evidence from our experimental data has shown that ATAD3A oligomerization requires the accumulation of astrocytic glycogen stress granules. Under physiological conditions, ATAD3A does not oligomerize, and mitochondria do not exhibit obvious dysfunction in nonglycogen stress granule-deposited cells. To explore what candidate partners are involved with ATAD3A. The proximity-biotinylating enzyme TurboID was reconstituted with ATAD3A to detect biotinylated proteins adjacent to ATAD3A. We next constructed a stable ATAD3A-TurboID cell line (or primary astrocytes). Pulldown biotinylated proteins were subjected to quantitative high-resolution mass spectrometry. Based on the above mass spectrometry data and a series of experimental results, we found that: glycogen-laden astrocytes in the ischemic penumbra undergo HDAC3-dependent mitochondrial fragmentation via a stress granule-mediated mechanism, exacerbating neuronal injury and hindering functional recovery. Mechanistic studies demonstrate that glycogen aggregates sequester cytoplasmic HDAC3, enabling its translocation to mitochondria. There, HDAC3 deacetylates outer mitochondrial membrane protein ATAD3A, promoting oligomerization-driven mitochondrial fission. Astrocyte-specific ATAD3A ablation prevents stroke-induced synaptic disorganization, neural circuit disruption, and cognitive deficits. Therapeutically, combined administration of cotadutide (a glycogen-depleting GLP-1/GCGR agonist) and HDAC3 inhibitor RGFP966 reverses glycogen accumulation, rescues mitochondrial architecture/function, and restores synaptic plasticity and circuit reorganization, thereby accelerating sensorimotor recovery.
2025-06-06 | PXD064694 | Pride
Project description:Ischemic stroke induces pathological glycogen deposition in astrocytes, but its role in post-injury neural dysfunction remains undefined. We firstly intend to identify the glycogen granule proteome after ischemic stroke via glycogen pulldown for protein mass spectrometry detection. KEGG pathway analysis of the glycogen granule proteome revealed highly enriched mitochondrial-related functional signals, such as respiratory chain complexes, mitochondrial respirasomes, and mitochondrial membrane protein complexes. GO functional annotation of biological processes revealed enrichment of genes related to mitochondrial electron transport, respiratory chain complexes, and mitochondrial ATP synthesis. To explore detailed mitochondrial biological processes in detail, we summarized mitochondrial function gene sets from the mitoproteome database and intersected them with many glycogen-enriched proteins. The data revealed that glycogen stress granules are related mainly to oxidative phosphorylation subunits, assembly factors and electron carriers; mitochondrial dynamics (such as MFF, DNM1L, and GDAP1), homeostasis, and quality control (such as AFG3L2, CLPB, and ATAD3A). Evidence from our experimental data has shown that ATAD3A oligomerization requires the accumulation of astrocytic glycogen stress granules. Under physiological conditions, ATAD3A does not oligomerize, and mitochondria do not exhibit obvious dysfunction in nonglycogen stress granule-deposited cells. To explore what candidate partners are involved with ATAD3A. The proximity-biotinylating enzyme TurboID was reconstituted with ATAD3A to detect biotinylated proteins adjacent to ATAD3A. We next constructed a stable ATAD3A-TurboID cell line (or primary astrocytes). Pulldown biotinylated proteins were subjected to quantitative high-resolution mass spectrometry. Based on the above mass spectrometry data and a series of experimental results, we found that: glycogen-laden astrocytes in the ischemic penumbra undergo HDAC3-dependent mitochondrial fragmentation via a stress granule-mediated mechanism, exacerbating neuronal injury and hindering functional recovery. Mechanistic studies demonstrate that glycogen aggregates sequester cytoplasmic HDAC3, enabling its translocation to mitochondria. There, HDAC3 deacetylates outer mitochondrial membrane protein ATAD3A, promoting oligomerization-driven mitochondrial fission. Astrocyte-specific ATAD3A ablation prevents stroke-induced synaptic disorganization, neural circuit disruption, and cognitive deficits. Therapeutically, combined administration of cotadutide (a glycogen-depleting GLP-1/GCGR agonist) and HDAC3 inhibitor RGFP966 reverses glycogen accumulation, rescues mitochondrial architecture/function, and restores synaptic plasticity and circuit reorganization, thereby accelerating sensorimotor recovery.
2025-06-06 | PXD064400 | Pride
Project description:Ischemic stroke induces pathological glycogen deposition in astrocytes, but its role in post-injury neural dysfunction remains undefined. We firstly intend to identify the glycogen granule proteome after ischemic stroke via glycogen pulldown for protein mass spectrometry detection. KEGG pathway analysis of the glycogen granule proteome revealed highly enriched mitochondrial-related functional signals, such as respiratory chain complexes, mitochondrial respirasomes, and mitochondrial membrane protein complexes. GO functional annotation of biological processes revealed enrichment of genes related to mitochondrial electron transport, respiratory chain complexes, and mitochondrial ATP synthesis. To explore detailed mitochondrial biological processes in detail, we summarized mitochondrial function gene sets from the mitoproteome database and intersected them with many glycogen-enriched proteins. The data revealed that glycogen stress granules are related mainly to oxidative phosphorylation subunits, assembly factors and electron carriers; mitochondrial dynamics (such as MFF, DNM1L, and GDAP1), homeostasis, and quality control (such as AFG3L2, CLPB, and ATAD3A). Evidence from our experimental data has shown that ATAD3A oligomerization requires the accumulation of astrocytic glycogen stress granules. Under physiological conditions, ATAD3A does not oligomerize, and mitochondria do not exhibit obvious dysfunction in nonglycogen stress granule-deposited cells. To explore what candidate partners are involved with ATAD3A. The proximity-biotinylating enzyme TurboID was reconstituted with ATAD3A to detect biotinylated proteins adjacent to ATAD3A. We next constructed a stable ATAD3A-TurboID cell line (or primary astrocytes). Pulldown biotinylated proteins were subjected to quantitative high-resolution mass spectrometry. Based on the above mass spectrometry data and a series of experimental results, we found that: glycogen-laden astrocytes in the ischemic penumbra undergo HDAC3-dependent mitochondrial fragmentation via a stress granule-mediated mechanism, exacerbating neuronal injury and hindering functional recovery. Mechanistic studies demonstrate that glycogen aggregates sequester cytoplasmic HDAC3, enabling its translocation to mitochondria. There, HDAC3 deacetylates outer mitochondrial membrane protein ATAD3A, promoting oligomerization-driven mitochondrial fission. Astrocyte-specific ATAD3A ablation prevents stroke-induced synaptic disorganization, neural circuit disruption, and cognitive deficits. Therapeutically, combined administration of cotadutide (a glycogen-depleting GLP-1/GCGR agonist) and HDAC3 inhibitor RGFP966 reverses glycogen accumulation, rescues mitochondrial architecture/function, and restores synaptic plasticity and circuit reorganization, thereby accelerating sensorimotor recovery.
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