Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow

Vartika Mishra, Diane B. Re, Virginia Verche, Mariano J. Alvarez, Alessandro Vasciaveo, Arnaud Jacquier, Paschalis-Tomas Doulias, Todd M. Greco, Monica Nizzardo, Dimitra Papadimitriou, Tetsuya Nagata, Paola Rinchetti, Eduardo J. Perez-Torres, Kristin A. Politi, Burcin Ikiz, Kevin Clare, Manuel E. Than, Stefania Corti, Harry Ischiropoulos, Francesco Lotti, Andrea Califano () and Serge Przedborski ()
Additional contact information
Vartika Mishra: Columbia University
Diane B. Re: Center for Motor Neuron Biology and Diseases, Columbia University
Virginia Verche: Columbia University
Mariano J. Alvarez: Columbia University
Alessandro Vasciaveo: Columbia University
Arnaud Jacquier: Columbia University
Paschalis-Tomas Doulias: Children’s Hospital of Philadelphia Research Institute and the University of Pennsylvania
Todd M. Greco: Children’s Hospital of Philadelphia Research Institute and the University of Pennsylvania
Monica Nizzardo: Columbia University
Dimitra Papadimitriou: Columbia University
Tetsuya Nagata: Columbia University
Paola Rinchetti: Columbia University
Eduardo J. Perez-Torres: Columbia University
Kristin A. Politi: Columbia University
Burcin Ikiz: Columbia University
Kevin Clare: Columbia University
Manuel E. Than: Protein Crystallography Group, Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)
Stefania Corti: University of Milan, Neurology Unit, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico
Harry Ischiropoulos: Children’s Hospital of Philadelphia Research Institute and the University of Pennsylvania
Francesco Lotti: Columbia University
Andrea Califano: Center for Motor Neuron Biology and Diseases, Columbia University
Serge Przedborski: Columbia University

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19177-y

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