TY - JOUR
T1 - Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow
AU - Mishra, Vartika
AU - Re, Diane B.
AU - Le Verche, Virginia
AU - Alvarez, Mariano J.
AU - Vasciaveo, Alessandro
AU - Jacquier, Arnaud
AU - Doulias, Paschalis Tomas
AU - Greco, Todd M.
AU - Nizzardo, Monica
AU - Papadimitriou, Dimitra
AU - Nagata, Tetsuya
AU - Rinchetti, Paola
AU - Perez-Torres, Eduardo J.
AU - Politi, Kristin A.
AU - Ikiz, Burcin
AU - Clare, Kevin
AU - Than, Manuel E.
AU - Corti, Stefania
AU - Ischiropoulos, Harry
AU - Lotti, Francesco
AU - Califano, Andrea
AU - Przedborski, Serge
N1 - Funding Information:
We thank Marc Tessier-Lavigne for his support and critical comments on this manuscript and for providing reagents for assays on DR6, Genentech for providing us with necessary reagents and mouse lines to study DR6, Lawrence S. Shapiro for guidance with the liquid chromatography work, Dimitar Nikolov and Jean-Pierre Julien for generously providing recombinant E2 fragment and SOD1 recombinants and Radhika Pradhan, Vernice Jackson-Lewis, James Caicedo and Norma Romero for technical expertize. Drs. M. De Rosa and C. Doege (Molecular Biology/Molecular Genetics Core of the New York Nutrition Obesity Research Center [P30 DK26687-40]) provided technical support and advice regarding the RNAscope studies. S.P. is supported by the Department of Defense (W81XWH-13-0416), the National Institute of Health (NS107442, NS117583, NS111176, AG064596), and Project-ALS. A.C. is supported by the NIH grants U54 CA209997 (Cancer Systems Biology Consortium), R35 CA197745 (NCI Outstanding Investigator Award), S10 OD012351 and S10 OD021764 (Shared Instrument Grants). D.B.R. is the recipient of a career development award from the NIEHS Center for Environmental Health in Northern Manhattan (ES009089). A.V. is supported by the Early Investigator Research Award from the US Department of Defense (W81XWH19-1-0337). S.C., M.N., P.R., are supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 778003.
Publisher Copyright:
© 2020, The Author(s).
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-19177-y
DO - 10.1038/s41467-020-19177-y
M3 - Article
AN - SCOPUS:85094965228
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5579
ER -