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P2X7 Receptor is Involved in Mitochondrial Dysfunction Induced by Extracellular Alpha Synuclein in Neuroblastoma
Anna Wilkaniec1, Magdalena Cieślik1, Emilia Murawska2
1Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences Pawińskiego 5, 02-106 Warsaw, Poland.
Abstract:
The purinergic P2X7 receptor (P2X7R) belongs to a family of trimeric ion channels that are gated by extracellular adenosine 5'-triphosphate (ATP). Several studies have pointed to a role of P2X7R-dependent signalling in Parkinson's disease (PD)-related neurodegeneration. The pathology of (PD) is characterized by the formation of insoluble alpha-synuclein (α-Syn) aggregates-Lewy bodies, but the mechanisms underlying α-Syn-induced dopaminergic cell death are still partially unclear. Our previous studies indicate that extracellular α-Syn directly interact with neuronal P2X7R and induces intracellular free calcium mobilization in neuronal cells. The main objective of this study was to examine the involvement of P2X7R receptor in α-Syn-induced mitochondrial dysfunction and cell death. We found that P2X7R stimulation is responsible for α-Syn-induced oxidative stress and activation of the molecular pathways of programmed cell death. Exogenous α-Syn treatment led to P2X7R-dependent decrease in mitochondrial membrane potential as well as elevation of mitochondrial ROS production resulting in breakdown of cellular energy production. Moreover, P2X7R-dependent deregulation of AMP-activated protein kinase as well as decrease in parkin protein level could be responsible for α-Syn-induced mitophagy impairment and accumulation of dysfunctional mitochondria. P2X7R might be putative pharmacological targets in molecular mechanism of extracellular α-Syn toxicity.
Insights
The purinergic P2X7 receptor (P2X7R) mediates alpha-synuclein toxicity in Parkinson's disease models. P2X7R activation drives mitochondrial dysfunction and cell death, suggesting it as a therapeutic target.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Parkinson's disease (PD) involves alpha-synuclein (α-Syn) aggregation and dopaminergic neuron loss.
- The purinergic P2X7 receptor (P2X7R) is implicated in neurodegeneration, potentially linking α-Syn to cell death.
- Extracellular α-Syn interacts with neuronal P2X7R, causing calcium influx.
Purpose of the Study:
- To investigate the role of P2X7R in α-Syn-induced mitochondrial dysfunction and dopaminergic cell death.
- To elucidate the molecular mechanisms by which P2X7R contributes to α-Syn toxicity in Parkinson's disease.
Main Methods:
- Treatment of neuronal cells with exogenous α-Syn.
- Assessment of P2X7R activation, calcium mobilization, and mitochondrial function (membrane potential, ROS production).
- Analysis of cellular energy production, AMP-activated protein kinase (AMPK) activity, and parkin levels.
Main Results:
- P2X7R stimulation mediates α-Syn-induced oxidative stress and programmed cell death pathways.
- α-Syn treatment leads to P2X7R-dependent mitochondrial dysfunction, including reduced membrane potential and increased ROS.
- P2X7R activation impairs mitophagy via AMPK and parkin deregulation, causing accumulation of damaged mitochondria.
Conclusions:
- P2X7R activation is a key mediator of extracellular α-Syn toxicity in dopaminergic neurons.
- Targeting P2X7R may offer a novel therapeutic strategy for Parkinson's disease.
- P2X7R plays a critical role in α-Syn-induced mitochondrial damage and impaired cellular quality control mechanisms.
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