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

Nat Commun. 2020 Nov 4;11(1):5579. doi: 10.1038/s41467-020-19177-y.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Amyotrophic Lateral Sclerosis / enzymology
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Animals
  • Astrocytes / metabolism*
  • Cell Communication / physiology*
  • Cell Death / physiology*
  • Cells, Cultured
  • Computational Biology
  • Disease Models, Animal
  • Gene Knockdown Techniques
  • Gene Silencing
  • Humans
  • Ligands
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Transgenic
  • Motor Neurons / metabolism*
  • Proteomics
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism
  • Superoxide Dismutase-1 / genetics
  • Superoxide Dismutase-1 / metabolism*


  • Amyloid beta-Protein Precursor
  • Aplp1 protein, mouse
  • Ligands
  • RNA, Small Interfering
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf21 protein, mouse
  • Superoxide Dismutase-1
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse