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P2X7 Receptor Activation Modulates Autophagy in SOD1-G93A Mouse Microglia
Paola Fabbrizio1,2, Susanna Amadio1, Savina Apolloni1
1IRCCS Santa Lucia Foundation, Experimental NeuroscienceRome, Italy.
Abstract:
Autophagy and inflammation play determinant roles in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), an adult-onset neurodegenerative disease characterized by deterioration and final loss of upper and lower motor neurons (MN) priming microglia to sustain neuroinflammation and a vicious cycle of neurodegeneration. Given that extracellular ATP through P2X7 receptor constitutes a neuron-to-microglia alarm signal implicated in ALS, and that P2X7 affects autophagy in immune cells, we have investigated if autophagy can be directly triggered by P2X7 activation in primary microglia from superoxide dismutase 1 (SOD1)-G93A mice. We report that P2X7 enhances the expression of the autophagic marker microtubule-associated protein 1 light chain 3 (LC3)-II, via mTOR pathway and concomitantly with modulation of anti-inflammatory M2 microglia markers. We also demonstrate that the autophagic target SQSTM1/p62 is decreased in SOD1-G93A microglia after a short stimulation of P2X7, but increased after a sustained challenge. These effects are prevented by the P2X7 antagonist A-804598, and the autophagy/phosphoinositide-3-kinase inhibitor wortmannin (WM). Finally, a chronic in vivo treatment with A-804598 in SOD1-G93A mice decreases the expression of SQSTM1/p62 in lumbar spinal cord at end stage of disease. These data identify the modulation of the autophagic flux as a novel mechanism by which P2X7 activates ALS-microglia, to be considered for further investigations in ALS.
Insights
Extracellular ATP acting on P2X7 receptors activates autophagy in microglia, a key process in Amyotrophic Lateral Sclerosis (ALS). This P2X7 receptor activation influences the autophagic flux, offering a potential therapeutic target for ALS.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Autophagy and inflammation are critical in Amyotrophic Lateral Sclerosis (ALS) pathogenesis.
- Extracellular ATP signaling via P2X7 receptors acts as a danger signal in ALS, influencing microglia and neuroinflammation.
- P2X7 receptor activation is known to affect autophagy in immune cells.
Purpose of the Study:
- To investigate if P2X7 receptor activation directly triggers autophagy in primary microglia from SOD1-G93A mice, a model of ALS.
- To explore the role of P2X7-mediated autophagy in modulating microglial inflammatory markers and autophagic flux.
Main Methods:
- Primary microglia isolated from SOD1-G93A mice were stimulated via P2X7 receptors.
- Autophagy markers (LC3-II, SQSTM1/p62) and microglial polarization markers were analyzed.
- Pharmacological inhibitors (P2X7 antagonist A-804598, wortmannin) and in vivo treatment were employed.
Main Results:
- P2X7 receptor activation enhanced the expression of the autophagic marker LC3-II via the mTOR pathway.
- SQSTM1/p62 levels showed differential modulation: decreased with short stimulation, increased with sustained P2X7 activation.
- P2X7 antagonism and autophagy inhibition prevented these effects; in vivo treatment reduced SQSTM1/p62 in the spinal cord of ALS mice.
Conclusions:
- P2X7 receptor activation directly modulates autophagic flux in ALS microglia.
- This modulation represents a novel mechanism linking P2X7 signaling to microglial activation in ALS.
- Targeting P2X7-mediated autophagy may offer a new therapeutic strategy for ALS.
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