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Published on: August 10, 2018
MicroRNA-125b regulates microglia activation and motor neuron death in ALS
C Parisi1,2, G Napoli2, S Amadio1,2
1CNR-Institute of Cell Biology and Neurobiology, Via del Fosso di Fiorano 65, Rome 00143, Italy.
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.
Insights
Microglia self-regulation is key in neurodegeneration. This study reveals miR-125b worsens amyotrophic lateral sclerosis (ALS) by inhibiting A20, prolonging harmful NF-κB activation and motor neuron damage.
Area of Science:
- Neuroscience
- Immunology
- Molecular Biology
Background:
- Microglia play a crucial role in neuroinflammation, a key factor in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS).
- Persistent activation of the nuclear factor-kappa B (NF-κB) pathway in microglia contributes to motor neuron injury in ALS, but negative regulatory mechanisms are poorly understood.
- The ubiquitin-editing enzyme A20 is a known inhibitor of the NF-κB pathway, and microRNAs are emerging as critical regulators of neuroinflammation, with some implicated in ALS.
Purpose of the Study:
- To investigate the interplay between microRNA-125b (miR-125b) and the A20 protein in modulating classical NF-κB signaling within microglia.
- To elucidate the role of this miR-125b-A20 interaction in the context of amyotrophic lateral sclerosis (ALS) pathogenesis and its impact on motor neurons.
Main Methods:
- Utilized cell culture models of microglia and motor neurons.
- Investigated the regulatory effects of miR-125b on A20 protein expression and NF-κB pathway activation.
- Examined the role of the purinergic P2X7 receptor in the observed signaling pathway.
- Assessed the impact of modulating miR-125b and A20 levels on motor neuron survival.
Main Results:
- Identified a pathological circuit where miR-125b suppresses A20 function, leading to sustained and detrimental P2X7 receptor-dependent NF-κB activation in microglia.
- Demonstrated that this prolonged NF-κB activation exacerbates motor neuron injury in an ALS context.
- Showed that inhibiting miR-125b and consequently restoring A20 levels promotes motor neuron survival.
Conclusions:
- miR-125b acts as a key mediator in the pathological dynamics of microglia during ALS.
- The miR-125b-A20 axis represents a critical regulatory mechanism for NF-κB signaling in microglia with significant implications for neuroinflammation and neurodegeneration.
- Targeting miR-125b offers a potential therapeutic strategy for preserving motor neuron function in ALS.
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