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Aberrant astrocyte protein secretion contributes to altered neuronal development in diverse disorders

ABSTRACT: Astrocytes negatively impact neuronal development in a range of neurodevelopmental disorders (NDs), however how they do this, and if mechanisms are shared across multiple disorders, is not known. We developed an in vitro system to ask how astrocyte protein secretion and gene expression change in 3 genetic NDs. This identified disorder specific changes, as well as core proteins that are increased in release in all 3 NDs. ND astrocytes increase release of Igfbp2, and blocking Igfbp2 partially rescues the neurite outgrowth inhibitory effects of Rett Syndrome astrocytes. We identified that ND astrocytes upregulate release of Bmp6, which acts on astrocytes themselves and is upstream of astrocyte secretion changes in NDs. Blocking Bmp signaling in Fragile X Syndrome astrocytes reverses the inhibitory effects of FXS astrocytes on neuronal development. We provide a resource of astrocyte secreted proteins in health and NDs, as well as novel targets for intervention in diverse NDs.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Jolene Diedrich

LAB HEAD: Nicola Allen

PROVIDER: PXD015996 | Pride | 2022-07-11

REPOSITORIES: Pride

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Project description:MartínJiménez2017 - Genome-scale reconstruction of the human astrocyte metabolic network This model is described in the article: Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network. Martín-Jiménez CA, Salazar-Barreto D, Barreto GE, González J. Front Aging Neurosci 2017; 9: 23 Abstract: Astrocytes are the most abundant cells of the central nervous system; they have a predominant role in maintaining brain metabolism. In this sense, abnormal metabolic states have been found in different neuropathological diseases. Determination of metabolic states of astrocytes is difficult to model using current experimental approaches given the high number of reactions and metabolites present. Thus, genome-scale metabolic networks derived from transcriptomic data can be used as a framework to elucidate how astrocytes modulate human brain metabolic states during normal conditions and in neurodegenerative diseases. We performed a Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network with the purpose of elucidating a significant portion of the metabolic map of the astrocyte. This is the first global high-quality, manually curated metabolic reconstruction network of a human astrocyte. It includes 5,007 metabolites and 5,659 reactions distributed among 8 cell compartments, (extracellular, cytoplasm, mitochondria, endoplasmic reticle, Golgi apparatus, lysosome, peroxisome and nucleus). Using the reconstructed network, the metabolic capabilities of human astrocytes were calculated and compared both in normal and ischemic conditions. We identified reactions activated in these two states, which can be useful for understanding the astrocytic pathways that are affected during brain disease. Additionally, we also showed that the obtained flux distributions in the model, are in accordance with literature-based findings. Up to date, this is the most complete representation of the human astrocyte in terms of inclusion of genes, proteins, reactions and metabolic pathways, being a useful guide for in-silico analysis of several metabolic behaviors of the astrocyte during normal and pathologic states. This model is hosted on BioModels Database and identified by: MODEL1608180000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Aberrant astrocyte protein secretion contributes to altered neuronal development in diverse disorders

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