P2X7 receptor mediates extracellular alpha-synuclein-induced mitochondrial dysfunction in neuroblastoma SH-SY5Y cells

• Autorzy: Wilkaniec A. , Lenkiewicz A.M. , Czapski G.A. , Sulkowski G. , Adamczyk A.
• Języki publikacji: EN

Abstrakty

EN

INTRODUCTION: α‑Synuclein (ASN) accumulation and mitochondrial dysfunction are central to the pathogenesis of most forms of Parkinson’s disease (PD) and appear to intersect, but how the two are related to each other has remained elusive. Recent research emphasised the important role of purinergic signalling dysfunction in PD. While the significant role of purinergic P2 family receptors in mitochondrial dysfunction is well known, the interaction of extracellular soluble ASN with purinergic receptors as well as the involvement of this interaction on mitochondria are not yet studied. AIM(S): The aim of this study was to investigate the effect of ASN on P2 purinergic signalling and the involvement of purinergic receptors in mitochondrial dysfunction. METHOD(S): As a research model we used neuroblastoma SH-SY5Y cell line as well as rat synaptoneurosomes treated with exogenous soluble ASN. The experiments were performed using spectrofluorometric, radiochemical and immunochemical methods. RESULTS: We found that exogenous ASN directly interacts with purinergic P2X7 receptor leading to its activation and intracellular free calcium mobilization in neuronal cells and nerve endings. Activation of P2X7 receptors leads to pannexin 1 recruitment and increased ATP release. Furthermore, ASN treatment induced mitochondrial dysfunction: changes in mitochondrial redox state, decrease in mitochondria membrane potential and elevation of mitochondrial superoxide production. This resulted in decreased synthesis of ATP and ultimately cell death. Importantly, treatment with non-selective (PPADS) or selective (AZ 11645373) P2X7 antagonist reversed the ASN-induced mitochondrial damage and prevented SH-SY5Y cells death. CONCLUSIONS: Our data indicated that P2X7 receptor activation is responsible for ASN-induced mitochondrial dysfunction. Thus, interference with P2X7 signalling seems to be a promising strategy for the prevention or therapy of PD and other neurodegenerative disorders. FINANCIAL SUPPORT: Supported by the NSC grant 2013/09/D/NZ3/0135.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2017
• Tom: 77
• Numer: Suppl.1
• Opis fizyczny: p.68

Twórcy

autor

Wilkaniec A.

• Department of Cellular Signaling, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Lenkiewicz A.M.

• Department of Cellular Signaling, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Czapski G.A.

• Department of Cellular Signaling, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Sulkowski G.

• Laboratory of Pathoneurochemistry, Department of Neurochemistry, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland

autor

Adamczyk A.

• Department of Cellular Signaling, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland