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Control (healthy) iPSC-derived astrocytes treated with: Media (control), TNFa 100ug/ml, Monomeric aSYN 10uM, or Fibril aSYN 10uM

ABSTRACT: Control (healthy) iPSC-derived astrocytes treated with: Media (control), TNFa 100ug/ml, Monomeric aSYN 10uM, or Fibril aSYN 10uM

PROVIDER: PRJNA701928 | ENA |

REPOSITORIES: ENA

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Control (healthy) iPSC-derived astrocytes treated with: Media (control), TNFa 100ug/ml, Monomeric aSYN 10uM, or Fibril aSYN 10uM

Project description:The overall goal was to identify changes in gene expression following treatment with TNFa, monomeric, or fibril aSYN compared to control (untreated). Alpha-synuclein (αSYN) protein has been observed in reactive astrocytes in PD patients’ brains, raising the question of how αSYN, neuroinflammation, and astrocytes interact in PD pathogenesis. Here, we examined the cellular changes triggered by tumor necrosis factor alpha (TNFα) and different αSYN species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNFα displayed a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the NF-kB pathway, and release of pro-inflammatory cytokines, whereas those treated with high molecular weight αSYN fibrils acquired a reactive antigen (cross-)presenting phenotype with upregulation of MHC genes and increased HLA-DR/DQ/DP and HLA-F molecules at the cell surface. Surprisingly, cell surface location of MHC proteins was abrogated by larger F110 fibrils polymorph, despite the upregulation of MHC genes. A proteomics investigation further confirmed a direct interaction between astrocytic MHC proteins and αSYN fibril peptides. Interestingly, TNFα and αSYN fibrils competed to drive the astrocyte immune reactive response. The astrocyte immune responses were accompanied by an impaired ATP-generating mitochondrial respiration, which was exacerbated in PD astrocytes containing a PARK2-variant. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors.

2021-02-16 | GSE166768 | GEO

Control (healthy) iPSC-derived astrocytes treated with: Media (control) or aSYN F110 10uM

Project description:Control (healthy) iPSC-derived astrocytes treated with: Media (control) or aSYN F110 10uM

| PRJNA701929 | ENA

Control (healthy) iPSC-derived astrocytes treated with: Media (control) or aSYN F110 10uM

Project description:The overall goal was to identify changes in gene expression following treatment with aSYN F110 compared to control (untreated). Alpha-synuclein (αSYN) protein has been observed in reactive astrocytes in PD patients’ brains, raising the question of how αSYN, neuroinflammation, and astrocytes interact in PD pathogenesis. Here, we examined the cellular changes triggered by tumor necrosis factor alpha (TNFα) and different αSYN species in astrocytes derived from induced pluripotent stem cells. Human astrocytes treated with TNFα displayed a strong reactive pro-inflammatory phenotype with upregulation of pro-inflammatory gene networks, activation of the NF-kB pathway, and release of pro-inflammatory cytokines, whereas those treated with high molecular weight αSYN fibrils acquired a reactive antigen (cross-)presenting phenotype with upregulation of MHC genes and increased HLA-DR/DQ/DP and HLA-F molecules at the cell surface. Surprisingly, cell surface location of MHC proteins was abrogated by larger F110 fibrils polymorph, despite the upregulation of MHC genes. A proteomics investigation further confirmed a direct interaction between astrocytic MHC proteins and αSYN fibril peptides. Interestingly, TNFα and αSYN fibrils competed to drive the astrocyte immune reactive response. The astrocyte immune responses were accompanied by an impaired ATP-generating mitochondrial respiration, which was exacerbated in PD astrocytes containing a PARK2-variant. Our data provide evidence for astrocytic involvement in PD pathogenesis and reveal their complex immune reactive responses to exogenous stressors.

2021-02-16 | GSE166769 | GEO

Transcription profiling of Neisseria meningitidis strain MC58 grown on RPMI agar containing 10uM Transferrin, 10uM Lactoferrin, 1uM Haemoglobin, or 20uM Ferric chloride

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Detection of structure-specific protein–protein interactions of alpha-synuclein

Project description:Parkinson’s disease (PD) is a neurodegenerative disorder associated with the accumulation of intraneuronal protein aggregates called Lewy bodies. These inclusions contain aberrantly folded and aggregated alpha-synuclein (aSyn), a key protein involved in the pathology of PD, for which the mechanisms of toxicity are still largely unknown. Recent studies suggest that the conformational changes occurring during aSyn aggregation process can be expected to lead to alterations in the interactome of aSyn. Therefore, identifying changes in the interactome of monomeric and aggregated states of aSyn could help to understand the underlying molecular mechanisms of PD. Despite substantial efforts, current interactomics approaches do not enable determining structure-specific PPIs and their interaction interfaces on a proteome-wide scale. To address this limitation, we here applied the structural proteomics method limited proteolysis–mass spectrometry to systematically identify structure-specific PPIs of aSyn by probing protein structural alterations within cellular extracts upon treatment with monomeric and aggregated, fibrillar states of aSyn. Overall, we identified several previously known interactors of both monomeric and aggregated aSyn as well as novel putative structure-specific interactors including their interaction interfaces and protein binding parameters in situ. These results may constitute an important step in the understanding of how distinct structural states of disease-associated proteins are involved in disease mechanisms.

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Genome-wide Binding Potential and Regulatory Activity of the Glucocorticoid Receptor’s Monomeric and Dimeric Forms

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