Journal Article

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

Mariano J. Alvarez, Dimitra Papadimitriou, Francesco Lotti, Todd M. Greco, Kevin Clare, Alessandro Vasciaveo, Diane B. Re, Paola Rinchetti, Eduardo J. Perez-Torres, Stefania Corti, Manuel E. Than, Serge Przedborski, Paschalis Tomas Doulias, Vartika Mishra, Andrea Califano, Burcin Ikiz, Monica Nizzardo, Harry Ischiropoulos, Kristin A. Politi, Tetsuya Nagata, Virginia Le Verche, Arnaud Jacquier

2020

Overview

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. Neuron-astrocyte communication plays a key role in pathophysiology, however systematic approaches to unveil it are limited. Here, the authors propose SEARCHIN, a multi-modal integrated workflow, as a tool to identify cross-compartment ligand-receptor interactions, applied to ALS models.

• Publisher: Springer Science and Business Media LLC,Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/51 / 13/89 / 14/19 / 14/32 / 631/378/1689 / 631/378/1689/1285 / 631/378/340 / 631/553/1833 / 64/110 / 64/60 / Alzheimer's disease / Amyloid beta-Protein Precursor / Amyloid beta-Protein Precursor - genetics / Amyloid beta-Protein Precursor - metabolism / Amyloid precursor protein / Amyotrophic Lateral Sclerosis / Amyotrophic Lateral Sclerosis - enzymology / Amyotrophic Lateral Sclerosis - genetics / Amyotrophic Lateral Sclerosis - metabolism / Animals / Astrocytes / Astrocytes - metabolism / Bioinformatics / Cell Communication / Cell Communication - physiology / Cell Death / Cell Death - physiology / Cell interactions / Cells, Cultured / Cellular communication / Computational Biology / Disease Models, Animal / Gene Knockdown Techniques / Gene Silencing / Humanities and Social Sciences / Humans / Ligands / Matrix Metalloproteinase 9 / Matrix Metalloproteinase 9 - metabolism / Mice / Mice, Transgenic / Motor Neurons / Motor Neurons - metabolism / multidisciplinary / Network analysis / Phenotypes / Proteomics / Q / Receptors / Receptors, Tumor Necrosis Factor / Receptors, Tumor Necrosis Factor - genetics / Receptors, Tumor Necrosis Factor - metabolism / RNA, Small Interfering / Science / Science (multidisciplinary) / Superoxide dismutase / Superoxide Dismutase-1 / Superoxide Dismutase-1 - genetics / Superoxide Dismutase-1 - metabolism / Transgenic mice / Workflow