![]() Indeed, although ALS is characterized by preferential death of motor neurons (MNs) 5, the contribution of aberrant cell-to-cell interactions involving non-neuronal cells such as glia to the neurodegenerative process is increasingly acknowledged 6. As a proof-of-concept for its utilization, we elect to study amyotrophic lateral sclerosis (ALS), a common fatal, paralytic disorder that provides an especially relevant context. Specifically, SEARCHIN implements a workflow that integrates several algorithms, such as ARACNe 1, VIPER 2, MINDy 3, and PrePPI 4, that were not originally designed to study the cell-cell communication process. As a result, high-throughput methodologies for the systematic prioritization of process-specific ligand–receptor interactions are critically needed, yet, still largely elusive.īy combining recent results on modeling transcriptional, signal transduction and other context-specific molecular interaction networks with proteomics, we propose an approach for the Systematic Elucidation and Assessment of Regulatory Cell-to-cell Interaction Networks (SEARCHIN) to prioritize cross-compartment ligand–receptor interactions that may mediate specific cellular phenotypes. Classical hypothesis-driven mechanistic elucidation of these intercellular signaling pathways requires complex, time-consuming, and laborious work to gradually restrict the number of molecular players that may mediate the cell-to-cell interaction of interest. The latter can range from the activation of specific immune response pathways to the aberrant reprogramming of cell state and even cell death. The rationale for the elucidation of mechanisms that mediate cell-to-cell communication processes is that ligands released by one cell type may induce specific changes in gene-product activity in one or more additional cell types, ultimately resulting in an observable molecular 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. Moreover, the DR6 knockdown in MNs of transgenic mutSOD1 mice attenuates the ALS-like phenotype. The inferred deleterious role of APP and DR6 is confirmed in vitro in models of ALS. 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. 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. 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. ![]() Nature Communications volume 11, Article number: 5579 ( 2020)Ĭell-to-cell communications are critical determinants of pathophysiological phenotypes, but methodologies for their systematic elucidation are lacking. Systematic elucidation of neuron-astrocyte interaction in models of amyotrophic lateral sclerosis using multi-modal integrated bioinformatics workflow ![]()
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