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Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow
Cell-to-cell communications are critical determinants of pathophysiological phenotypes, but methodologies for their systematic elucidation are lacking. Herein, we propose an approach for the Systematic Elucidation and Assessment of Regulatory Cell-to-cell Interaction Networks (SEARCHIN) to identify ...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642391/ https://www.ncbi.nlm.nih.gov/pubmed/33149111 http://dx.doi.org/10.1038/s41467-020-19177-y |
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author | Mishra, Vartika Re, Diane B. Le Verche, Virginia Alvarez, Mariano J. Vasciaveo, Alessandro Jacquier, Arnaud Doulias, Paschalis-Tomas Greco, Todd M. Nizzardo, Monica Papadimitriou, Dimitra Nagata, Tetsuya Rinchetti, Paola Perez-Torres, Eduardo J. Politi, Kristin A. Ikiz, Burcin Clare, Kevin Than, Manuel E. Corti, Stefania Ischiropoulos, Harry Lotti, Francesco Califano, Andrea Przedborski, Serge |
author_facet | Mishra, Vartika Re, Diane B. Le Verche, Virginia Alvarez, Mariano J. Vasciaveo, Alessandro Jacquier, Arnaud Doulias, Paschalis-Tomas Greco, Todd M. Nizzardo, Monica Papadimitriou, Dimitra Nagata, Tetsuya Rinchetti, Paola Perez-Torres, Eduardo J. Politi, Kristin A. Ikiz, Burcin Clare, Kevin Than, Manuel E. Corti, Stefania Ischiropoulos, Harry Lotti, Francesco Califano, Andrea Przedborski, Serge |
author_sort | Mishra, Vartika |
collection | PubMed |
description | Cell-to-cell communications are critical determinants of pathophysiological phenotypes, but methodologies for their systematic elucidation are lacking. Herein, we propose an approach for the Systematic Elucidation and Assessment of Regulatory Cell-to-cell Interaction Networks (SEARCHIN) to identify ligand-mediated interactions between distinct cellular compartments. To test this approach, we selected a model of amyotrophic lateral sclerosis (ALS), in which astrocytes expressing mutant superoxide dismutase-1 (mutSOD1) kill wild-type motor neurons (MNs) by an unknown mechanism. Our integrative analysis that combines proteomics and regulatory network analysis infers the interaction between astrocyte-released amyloid precursor protein (APP) and death receptor-6 (DR6) on MNs as the top predicted ligand-receptor pair. The inferred deleterious role of APP and DR6 is confirmed in vitro in models of ALS. Moreover, the DR6 knockdown in MNs of transgenic mutSOD1 mice attenuates the ALS-like phenotype. Our results support the usefulness of integrative, systems biology approach to gain insights into complex neurobiological disease processes as in ALS and posit that the proposed methodology is not restricted to this biological context and could be used in a variety of other non-cell-autonomous communication mechanisms. |
format | Online Article Text |
id | pubmed-7642391 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76423912020-11-10 Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow Mishra, Vartika Re, Diane B. Le Verche, Virginia Alvarez, Mariano J. Vasciaveo, Alessandro Jacquier, Arnaud Doulias, Paschalis-Tomas Greco, Todd M. Nizzardo, Monica Papadimitriou, Dimitra Nagata, Tetsuya Rinchetti, Paola Perez-Torres, Eduardo J. Politi, Kristin A. Ikiz, Burcin Clare, Kevin Than, Manuel E. Corti, Stefania Ischiropoulos, Harry Lotti, Francesco Califano, Andrea Przedborski, Serge Nat Commun Article Cell-to-cell communications are critical determinants of pathophysiological phenotypes, but methodologies for their systematic elucidation are lacking. Herein, we propose an approach for the Systematic Elucidation and Assessment of Regulatory Cell-to-cell Interaction Networks (SEARCHIN) to identify ligand-mediated interactions between distinct cellular compartments. To test this approach, we selected a model of amyotrophic lateral sclerosis (ALS), in which astrocytes expressing mutant superoxide dismutase-1 (mutSOD1) kill wild-type motor neurons (MNs) by an unknown mechanism. Our integrative analysis that combines proteomics and regulatory network analysis infers the interaction between astrocyte-released amyloid precursor protein (APP) and death receptor-6 (DR6) on MNs as the top predicted ligand-receptor pair. The inferred deleterious role of APP and DR6 is confirmed in vitro in models of ALS. Moreover, the DR6 knockdown in MNs of transgenic mutSOD1 mice attenuates the ALS-like phenotype. Our results support the usefulness of integrative, systems biology approach to gain insights into complex neurobiological disease processes as in ALS and posit that the proposed methodology is not restricted to this biological context and could be used in a variety of other non-cell-autonomous communication mechanisms. Nature Publishing Group UK 2020-11-04 /pmc/articles/PMC7642391/ /pubmed/33149111 http://dx.doi.org/10.1038/s41467-020-19177-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Mishra, Vartika Re, Diane B. Le Verche, Virginia Alvarez, Mariano J. Vasciaveo, Alessandro Jacquier, Arnaud Doulias, Paschalis-Tomas Greco, Todd M. Nizzardo, Monica Papadimitriou, Dimitra Nagata, Tetsuya Rinchetti, Paola Perez-Torres, Eduardo J. Politi, Kristin A. Ikiz, Burcin Clare, Kevin Than, Manuel E. Corti, Stefania Ischiropoulos, Harry Lotti, Francesco Califano, Andrea Przedborski, Serge Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow |
title | Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow |
title_full | Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow |
title_fullStr | Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow |
title_full_unstemmed | Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow |
title_short | Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow |
title_sort | systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642391/ https://www.ncbi.nlm.nih.gov/pubmed/33149111 http://dx.doi.org/10.1038/s41467-020-19177-y |
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