P2X7 Receptor is Involved in Mitochondrial Dysfunction Induced by Extracellular Alpha Synuclein in Neuroblastoma SH-SY5Y Cells.

Anna Wilkaniec,Emilia Murawska,Ewelina Pałasz,Magdalena Gąssowska-Dobrowolska,Magdalena Cieślik,Agata Adamczyk,Henryk Jęśko,Lidia Babiec

doi:10.3390/ijms21113959

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.

Highlights

Since adenosine 5 -triphosphate (ATP) was proposed as an extracellular signalling molecule with neurotransmitter properties, the function of the purinergic signalling has been thoroughly studied in the central nervous system (CNS)
A few studies demonstrate that oxidative stress and mitochondrial toxicity are the key events leading to cell death induced by P2X7 receptor (P2X7R) [13,35]
In line with those data, we showed for the first time that exogenous α-Syn leads to P2X7R-dependent deregulation of mitochondria function resulting in decrease in cellular energy production and cell death

Summary

Introduction

Since adenosine 5 -triphosphate (ATP) was proposed as an extracellular signalling molecule with neurotransmitter properties, the function of the purinergic signalling has been thoroughly studied in the central nervous system (CNS). Most studies of the extracellular actions of ATP connected with the short-term neurotransmission and neuromodulation events are related to P2X receptor-mediated Ca2+ permeability and membrane depolarization The activation of these ionotropic receptors is significant for Ca2+-induced intracellular signalling pathways [7,8] involved in physiological processes or pathological conditions [9]. It was demonstrated that the negative impact of aberrantly secreted α-Syn does not appear to involve internalization of this protein by the recipient neurons [18,19], but it depends on deregulation of various plasma membrane receptors most of which are Ca2+ channels [20] Based on these data, deregulation of P2X7R-dependent purinergic signalling may be an important factor related to α-Syn-induced pathology in PD. While the significant role of purinergic P2 family receptors in neurodegenerative disorders is well known, the relationship of extracellular α-Syn with neuronal purinergic receptors as well as the involvement of this interaction on mitochondria have not yet been studied

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