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

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.

Recent Insights into the Interplay of Alpha-Synuclein and Sphingolipid Signaling in Parkinson’s Disease

“…However, its mutation or overexpression disturbed the process, which was confirmed by the inhibition of insulin-like growth factor 1 (IGF-1)-induced Akt activation [81]. Reduced phosphorylation/activation of Akt kinase was also observed in ours' and others' studies in neuronal cells treated with exogenous ASN [31,82]. ASN was also shown to inhibit BDNF signaling, leading to DA cell death [83].…”

“…Sci. 2021, 22, x FOR PEER REVIEW 7 of 27 and others' studies in neuronal cells treated with exogenous ASN [31,82]. ASN was also shown to inhibit BDNF signaling, leading to DA cell death [83].…”

Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology

“…Apart from its direct association with mitochondria, α-Syn may also indirectly affect their function. It was previously demonstrated that monomeric species of α-Syn, that are internalized less efficiently than oligomers (Hoffmann et al, 2019 ), can preferentially bind to and activate neuronal purinergic P2X7 receptor (Wilkaniec et al, 2017 ), which leads to a decrease in mitochondria membrane potential as well as elevation of mitochondrial ROS production (Wilkaniec et al, 2020 ). Also, oligomeric species of α-Syn were shown to induce selective oxidation and nitrosylation of mitochondrial proteins, triggering mitochondrial swelling and neuronal cell death (Tapias et al, 2017 ; Ludtmann et al, 2018 ).…”

Antagonistic Roles of P2X7 and P2Y2 Receptors in Neurodegenerative Diseases

“…In vitro, α-synuclein induced P2X7R activation in SH-SY5Yderived dopaminergic neurons that modulated mitochondrial dysfunction, ATP release, recruitment of pannexin-1 and decreased ATP degradation, with consequent cell death (Wilkaniec et al, 2017, Wilkaniec et al, 2020.…”