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

被引:32
作者
Wilkaniec, Anna [1 ]
Cieslik, Magdalena [1 ]
Murawska, Emilia [2 ]
Babiec, Lidia [1 ]
Gassowska-Dobrowolska, Magdalena [1 ]
Palasz, Ewelina [1 ]
Jesko, Henryk [1 ]
Adamczyk, Agata [1 ]
机构
[1] Polish Acad Sci, Mossakowski Med Res Ctr, Dept Cellular Signalling, Pawinskiego 5, PL-02106 Warsaw, Poland
[2] Warsaw Univ, Inst Microbiol, Dept Appl Microbiol, Miecznikowa 1 St, PL-02096 Warsaw, Poland
关键词
alpha-synuclein; P2X7; receptor; mitochondria dysfunction; parkin; AMP-activated protein kinase; ACTIVATED PROTEIN-KINASE; BRILLIANT BLUE G; PREVENTS ATP EXCITOTOXICITY; GREEN FLUORESCENT PROTEIN; COMPLEX-I; DOPAMINERGIC-NEURONS; DEPENDENT ACTIVATION; SIGNALING PATHWAYS; PARKINSONS-DISEASE; SUBSTANTIA-NIGRA;
D O I
10.3390/ijms21113959
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (alpha-Syn) aggregates-Lewy bodies, but the mechanisms underlying alpha-Syn-induced dopaminergic cell death are still partially unclear. Our previous studies indicate that extracellular alpha-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 alpha-Syn-induced mitochondrial dysfunction and cell death. We found that P2X7R stimulation is responsible for alpha-Syn-induced oxidative stress and activation of the molecular pathways of programmed cell death. Exogenous alpha-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 alpha-Syn-induced mitophagy impairment and accumulation of dysfunctional mitochondria. P2X7R might be putative pharmacological targets in molecular mechanism of extracellular alpha-Syn toxicity.
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页数:27
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