Articolo in rivista, 2021, ENG, 10.1016/j.nbd.2021.105538

CXCR2 increases in ALS cortical neurons and its inhibition prevents motor neurons degeneration in vitro and improves neuromuscular function in SOD1G93A mice

Valentina La Cognata; Elisabetta Golini; Rosario Iemmolo; Sara Balletta; Giovanna Morello; Carla De Rosa; Ambra Villari; Sara Marinelli; Valentina Vacca; Gabriele Bonaventura; Paola Dell'Albani; Eleonora Aronica; Fabio Mammano; Silvia Mandillo; Sebastiano Cavallaro;

Institute for Biomedical Research and Innovation, National Research Council, Via P. Gaifami 18, Catania, CT, 95126, Institute for Biomedical Research and Innovation, National Research Council, Via P. Gaifami 18, 95126, Catania (CT), Italy, , Italy; Institute of Biochemistry and Cell Biology, National Research Council, Via E. Ramarini 32, Monterotondo Scalo, RM, 00015, Institute of Biochemistry and Cell Biology, National Research Council, Via E. Ramarini 32, 00015, Monterotondo scalo (RM), Italy, , Italy; Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, Amsterdam, 1105, Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, 1105 Amsterdam, The Netherlands, , , Netherlands; Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, Amsterdam, 1105, Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, 1105 Amsterdam, The Netherlands, , , Netherlands; Department of Physics and Astronomy "G. Galilei", University of Padua, Padova, Department of Physics and Astronomy "G. Galilei", University of Padua, Padova, Italy, , Italy

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease characterized by depletion of motor neurons (MNs), for which effective medical treatments are still required. Previous transcriptomic analysis revealed the up-regulation of C-X-C motif chemokine receptor 2 (CXCR2)-mRNA in a subset of sporadic ALS patients and SOD1G93A mice. Here, we confirmed the increase of CXCR2 in human ALS cortex, and showed that CXCR2 is mainly localized in cell bodies and axons of cortical neurons. We also investigated the effects of reparixin, an allosteric inhibitor of CXCR2, in degenerating human iPSC-derived MNs and SOD1G93A mice. In vitro, reparixin rescued MNs from apoptotic cell death, preserving neuronal morphology, mitochondrial membrane potential and cytoplasmic membrane integrity, whereas in vivo it improved neuromuscular function of SOD1G93A mice. Altogether, these data suggest a role for CXCR2 in ALS pathology and support its pharmacological inhibition as a candidate therapeutic strategy against ALS at least in a specific subgroup of patients.

Neurobiology of disease 160

Keywords

CXCR2, Amyotrophic lateral sclerosis, IL8, iPSC, Motor neurons, Neurodegeneration, Reparixin, SOD1G93A mouse

CNR authors

Iemmolo Rosario, Morello Giovanna, Bonaventura Gabriele, Villari Ambra, Vacca Valentina, Cavallaro Sebastiano, Dell Albani Paola, Golini Elisabetta, Mandillo Silvia, Marinelli Sara, Mammano Fabio, La Cognata Valentina

CNR institutes

IRIB – Istituto per la Ricerca e l'Innovazione Biomedica, IBBC – Istituto di Biochimica e Biologia Cellulare