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

Vartika Mishra, Diane B. Re, Virginia Le 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 LottiAndrea Califano, Serge Przedborski

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number5579
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - Dec 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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