Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow
| Autor: | Manuel E. Than, Burcin Ikiz, Virginia Le Verche, Paola Rinchetti, Arnaud Jacquier, Vartika Mishra, Harry Ischiropoulos, Todd M. Greco, Kristin A. Politi, Dimitra Papadimitriou, Mariano J. Alvarez, Kevin Clare, Francesco Lotti, Alessandro Vasciaveo, Paschalis Tomas Doulias, Serge Przedborski, Diane B. Re, Andrea Califano, Monica Nizzardo, Stefania Corti, Eduardo J. Perez-Torres, Tetsuya Nagata |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Proteomics General Physics and Astronomy Cell Communication Ligands Receptors Tumor Necrosis Factor Amyloid beta-Protein Precursor Mice 0302 clinical medicine Superoxide Dismutase-1 Amyloid precursor protein Amyotrophic lateral sclerosis RNA Small Interfering lcsh:Science Cells Cultured Motor Neurons Multidisciplinary biology Cell Death Phenotype medicine.anatomical_structure Matrix Metalloproteinase 9 Gene Knockdown Techniques Systems biology Science Systems analysis Context (language use) Mice Transgenic Molecular neuroscience General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences medicine Animals Humans Gene Silencing Mechanism (biology) Amyotrophic Lateral Sclerosis Computational Biology General Chemistry medicine.disease Disease Models Animal 030104 developmental biology Astrocytes biology.protein Diseases of the nervous system lcsh:Q Neuron Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-20 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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