title: MicroRNA-125b regulates microglia activation and motor neuron death in ALS.
abstract: Understanding the means by which microglia self-regulate the neuroinflammatory response helps modulating their reaction during neurodegeneration. In amyotrophic lateral sclerosis (ALS), classical NF-κB pathway is related to persistent microglia activation and motor neuron injury; however, mechanisms of negative control of NF-κB activity remain unexplored. One of the major players in the termination of classical NF-κB pathway is the ubiquitin-editing enzyme A20, which has recognized anti-inflammatory functions. Lately, microRNAs are emerging as potent fine-tuners of neuroinflammation and reported to be regulated in ALS, for instance, by purinergic P2X7 receptor activation. In this work, we uncover an interplay between miR-125b and A20 protein in the modulation of classical NF-κB signaling in microglia. In particular, we establish the existence of a pathological circuit in which termination of A20 function by miR-125b strengthens and prolongs the noxious P2X7 receptor-dependent activation of NF-κB in microglia, with deleterious consequences on motor neurons. We prove that, by restoring A20 levels, miR-125b inhibition then sustains motor neuron survival. These results introduce miR-125b as a key mediator of microglia dynamics in ALS.
authors.affiliation: CNR-Institute of Cell Biology and Neurobiology, Via del Fosso di Fiorano 65, Rome 00143, Italy.|Santa Lucia Foundation, Via del Fosso di Fiorano 65, Rome 00143, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Parisi
authors.affiliation: Santa Lucia Foundation, Via del Fosso di Fiorano 65, Rome 00143, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Napoli
authors.affiliation: CNR-Institute of Cell Biology and Neurobiology, Via del Fosso di Fiorano 65, Rome 00143, Italy.|Santa Lucia Foundation, Via del Fosso di Fiorano 65, Rome 00143, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Amadio
authors.affiliation: Santa Lucia Foundation, Via del Fosso di Fiorano 65, Rome 00143, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Spalloni
authors.affiliation: CNR-Institute of Cell Biology and Neurobiology, Via del Fosso di Fiorano 65, Rome 00143, Italy.|Santa Lucia Foundation, Via del Fosso di Fiorano 65, Rome 00143, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Apolloni
authors.affiliation: Santa Lucia Foundation, Via del Fosso di Fiorano 65, Rome 00143, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Longone
authors.affiliation: CNR-Institute of Cell Biology and Neurobiology, Via del Fosso di Fiorano 65, Rome 00143, Italy.|Santa Lucia Foundation, Via del Fosso di Fiorano 65, Rome 00143, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Volonté
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D016923:Cell Death; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D017628:Microglia / Q000276:immunology / Q000378:metabolism*; D009046:Motor Neurons / Q000502:physiology; D020125:Mutation, Missense; D061251:Primary Cell Culture; D034622:RNA Interference; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; C498144:Rela protein, mouse; C000606290:SOD1 protein, human; D051996:Transcription Factor RelA; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse