2. Academic Validation
  3. CXCR2 increases in ALS cortical neurons and its inhibition prevents motor neuron degeneration in vitro and improves neuromuscular function in SOD1G93A mice

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

  • Neurobiol Dis. 2021 Dec:160:105538. doi: 10.1016/j.nbd.2021.105538.
Valentina La Cognata 1,  Elisabetta Golini 2,  Rosario Iemmolo 3,  Sara Balletta 4,  Giovanna Morello 5,  Carla De Rosa 6,  Ambra Villari 7,  Sara Marinelli 8,  Valentina Vacca 9,  Gabriele Bonaventura 10,  Paola Dell'Albani 11,  Eleonora Aronica 12,  Fabio Mammano 13,  Silvia Mandillo 14,  Sebastiano Cavallaro 15
Affiliations

Affiliations

  • 1 Institute for Biomedical Research and Innovation, National Research Council, Via P. Gaifami 18, 95126 Catania, CT, Italy. Electronic address: [email protected].
  • 2 Institute of Biochemistry and Cell Biology, National Research Council, Via E. Ramarini 32, 00015 Monterotondo Scalo, RM, Italy. Electronic address: [email protected].
  • 3 Institute for Biomedical Research and Innovation, National Research Council, Via P. Gaifami 18, 95126 Catania, CT, Italy. Electronic address: [email protected].
  • 4 Institute of Biochemistry and Cell Biology, National Research Council, Via E. Ramarini 32, 00015 Monterotondo Scalo, RM, Italy. Electronic address: [email protected].
  • 5 Institute for Biomedical Research and Innovation, National Research Council, Via P. Gaifami 18, 95126 Catania, CT, Italy. Electronic address: [email protected].
  • 6 Institute of Biochemistry and Cell Biology, National Research Council, Via E. Ramarini 32, 00015 Monterotondo Scalo, RM, Italy. Electronic address: [email protected].
  • 7 Institute for Biomedical Research and Innovation, National Research Council, Via P. Gaifami 18, 95126 Catania, CT, Italy. Electronic address: [email protected].
  • 8 Institute of Biochemistry and Cell Biology, National Research Council, Via E. Ramarini 32, 00015 Monterotondo Scalo, RM, Italy. Electronic address: [email protected].
  • 9 Institute of Biochemistry and Cell Biology, National Research Council, Via E. Ramarini 32, 00015 Monterotondo Scalo, RM, Italy. Electronic address: [email protected].
  • 10 Institute for Biomedical Research and Innovation, National Research Council, Via P. Gaifami 18, 95126 Catania, CT, Italy. Electronic address: [email protected].
  • 11 Institute for Biomedical Research and Innovation, National Research Council, Via P. Gaifami 18, 95126 Catania, CT, Italy. Electronic address: [email protected].
  • 12 Department of (Neuro) Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Meibergdreef 9, 1105 Amsterdam, the Netherlands. Electronic address: [email protected].
  • 13 Institute of Biochemistry and Cell Biology, National Research Council, Via E. Ramarini 32, 00015 Monterotondo Scalo, RM, Italy; Department of Physics and Astronomy "G. Galilei", University of Padua, Padova, Italy. Electronic address: [email protected].
  • 14 Institute of Biochemistry and Cell Biology, National Research Council, Via E. Ramarini 32, 00015 Monterotondo Scalo, RM, Italy. Electronic address: [email protected].
  • 15 Institute for Biomedical Research and Innovation, National Research Council, Via P. Gaifami 18, 95126 Catania, CT, Italy. Electronic address: [email protected].
PMID: 34743985 DOI: 10.1016/j.nbd.2021.105538
Abstract

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.

Keywords

Amyotrophic lateral sclerosis; CXCR2; IL-8; Motor neurons; Neurodegeneration; Reparixin; SOD1G93A mouse; iPSC.

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