Death receptor-6 (DR6) on motor neuron was identified as possible disease modifier of Amyotrophic Lateral Sclerosis by the researchers of the Centro Dino Ferrari, University of Milan, IRCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico and Columbia University (New York). The study was published in eminent journal Nature Communications journal in November 2020.

ALS and motor neuron diseases are serious neurodegenerative diseases, characterized by the death of motor neurons in the Central Nervous System, the neurons that control skeletal muscles and thus voluntary movements. These diseases cause progressive weakness, muscle atrophy, deficiency in swallowing and difficulty in breathing with premature death. No effective therapies are currently available for ALS.

The mechanisms responsible for this selective degeneration are largely unknown, but cell-to-cell communications are critical determinants and might offer clues on neuronal susceptibility. In this work, 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 strategy, we selected a model of ALS, in which astrocytes expressing mutant superoxide dismutase-1 (mutSOD1) are toxic for wild-type motor neurons by an unknown mechanism. Our integrative analysis that combined proteomics and regulatory network analysis pointed out the interaction between astrocyte-released amyloid precursor protein (APP) and DR6 on motor neurons as the top predicted ligand-receptor pair. The inferred deleterious role of APP and DR6 was confirmed in vitro in models of ALS. Moreover, the DR6 knockdown in motor neurons of transgenic mutSOD1 mice ameliorated the ALS-like phenotype. Our results support the utility of integrative, systems biology approach to gain insights into complex neurobiological disease processes as in ALS.

Nonetheless, a deeper understanding of the molecular mechanisms underlying DR6 effects is needed to improve and allow translation in humans of this therapeutic modulation. Moreover, SEARCHINapproach might help to identify new therapeutic targets for ALS.

Prof. Corti, M.D., Ph.D., chief of the Neural Stem Cell Laboratory in the Neuroscience Division, Department of Pathophysiology and Transplantation, is co-author in the research. The research group included Dr. Nizzardo, PhD, and Dr. Rinchetti, PhD, members of Corti lab and researchers of the Centro Dino Ferrari, University of Milan, IRCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico. This study was guided by Prof. Przedborski at the Motor Neuron Center, Columbia University, a long-time collaborator of Corti’s group.

Our presented combination of computational multi-modal analysis followed by experimental validation offers an effective proof-of-principle for a generalizable methodology directed at elucidating cell-to-cell communication mechanisms and therapeutic target identification.

The research was financed by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 778003.

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For other information:

Prof. Stefania Corti

Centro Dino Ferrari, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico

Tel. +39 02 55033817

stefania.corti@unimi.it

Mishra V, Re DB, Le Verche V, Alvarez MJ, Vasciaveo A, Jacquier A, Doulias PT, Greco TM, Nizzardo M, Papadimitriou D, Nagata T, Rinchetti P, Perez-Torres EJ, Politi KA, Ikiz B, Clare K, Than ME, Corti S, Ischiropoulos H, Lotti F, Califano A, Przedborski S. 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. PMID: 33149111.