MicroRNA-125b regulates microglia activation and motor neuron death in ALS

C. Parisi, G. Napoli, S. Amadio, A. Spalloni, S. Apolloni, P. Longone, C. Volonte

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)531-541
Number of pages11
JournalCell Death and Differentiation
Volume23
Issue number3
DOIs
Publication statusPublished - Mar 1 2016

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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