Loss of ATG7 in Microglia Impairs UPR, Triggers Ferroptosis and Weakens Amyloid Pathology Control [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1207905 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer’s Disease (AD) is to contain proteotoxic amyloid β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ build-up, UPR reduction and increase oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation as they age.
2025-01-30 | GSE286094 | GEO
Project description:Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer’s Disease (AD) is to contain proteotoxic amyloid β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ build-up, UPR reduction and increase oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation as they age.
2025-01-30 | GSE286095 | GEO
Project description:Nrf2-dependent expression of numerous genes in Atg7-deficient livers was observed.
2016-06-21 | GSE65174 | GEO
Project description:Autophagy deficiency caused by conditional knockout of Atg7 results in severe hepatitis accompanied by abundant accumulation of p62. p62 stablizes Nrf2 by disrupting the association between Keap1 and Nrf2. To understand the pathogenesis of hepatitis under the autophagy deficiency, we examined gene expression profiles of livers from Atg7-null, Nrf2-null and Atg7-Nrf2 double mutant mice. Eight week old Atg7F/F:Mx1-Cre mice and Atg7F/F:Mx1-Cre:Nrf2-/- together with control mice were injected with pIpC. At 4 weeks after pIpC injection, total RNAs were purified from each mouse liver.
2010-10-14 | E-GEOD-20415 | biostudies-arrayexpress
Project description:Autophagy genes play an important role in the T cell activation and proliferation. We examined the role of ATG7 during the process of CD8 T cell memory formation. In the absence of ATG7, antigen-specific CD8 T cells failed to survive past the contraction phase and failed to give rise to memory cells. We used microarrays to examine the global programme of gene expression underlying changes introduced in the absence of the ATG7 gene and identified distinct classes genes varied their expression during this time-point. Mouse LCMV-specific CD8 T cells were isolated at day 8 post LCMV infection for RNA extraction and hybridization on Affymetrix microarrays. We sought to compare the gene expression profiles in wild-type cells and cells lacking the ATG7 gene during the peak of their expansion.
2014-10-26 | E-GEOD-57047 | biostudies-arrayexpress
Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.
2024-09-30 | GSE235179 | GEO
Project description:Transcriptome analysis of NesCre:Atg7 conditional knockout mice. Autophagy plays an important role in regulating protein metabolism and tissue homeostasis. Recent studies have reported that neural stem cell-specific Atg7 knockout mice (NesCre:Atg7f/f cKO mice) exhibit neonatal lethal due to severe neurodegeneration. However, the precise mechanisms of how neuronal fate is regulated by the autophagic pathway have not been elucidated. Here, we performed microarray experiments to analyze the changes in gene expression patterns in NesCre:Atg7 cKO mice. As a result, we could find a lot of candidate genes changed by Atg7 deficiency.
2022-10-07 | GSE214939 | GEO
Project description:Macroautophagy/autophagy is a catabolic process that targets a wide variety of cellular components including proteins, lipids, damaged organelles, and pathogens. The autophagy protein ATG7 is involved in autophagy initiation by facilitating the lipidation of LC3/GABARAPs at the growing autophagosomal membrane. ATG7 is important for normal cellular homeostasis as well as diseased state such as tumor initiation and progression in various tumors. A short isoform of ATG7, termed ATG7(2) in contrast to the full-length ATG7(1), is unable to perform the characterized ATG7 mediated autophagy lipidation activity. In this study, we found that ATG7(1) and ATG7(2) are not correlated in expression in human tissues. They have different patterns of expression indicating that these isoforms are involved in diverse cellular mechanisms. To address the functional role of the short ATG7(2) isoform, we performed mass spectrometry analysis of the protein interactome of ATG7(1) and ATG7(2). This revealed that whereas ATG7(1) interacts with the autophagy machinery, ATG7(2) interacts with key glycolysis and mitochondrial membrane proteins. Functional experiments showed that ATG7(2) expression mediates a decrease in glycolytic activity, opposite to the effects mediated by ATG7(1) expression. These findings suggest a molecular switch between main catabolic processes through isoform dependent expression of a key autophagy gene.
2024-04-15 | PXD040548 | Pride
Project description:Autophagy deficiency caused by conditional knockout of Atg7 results in severe hepatitis accompanied by abundant accumulation of p62. p62 stablizes Nrf2 by disrupting the association between Keap1 and Nrf2. To understand the pathogenesis of hepatitis under the autophagy deficiency, we examined gene expression profiles of livers from Atg7-null, Nrf2-null and Atg7-Nrf2 double mutant mice.
2010-10-15 | GSE20415 | GEO