Extracellular alpha-synuclein induces calpain-dependent overactivation of cyclin-dependent kinase 5 in PC12 cells

• Autorzy: Adamczyk A. , Gasowska M. , Wilkaniec A. , Cieslik M. , Czapski G. A.
• Języki publikacji: EN

Abstrakty

EN

α-Synuclein (ASN) secreted from neurons into the extracellular space affects the homeostasis of neighboring cells, but the pathophysiology of extracellular ASN remains largely unknown. The aim of the present study was to analyze the role of cyclin dependent kinase 5 (Cdk5) in molecular mechanism of extracellular ASN toxicity. We found that exogenously applied ASN evoked apoptotic cell death in a significant population of dopaminergic PC12 cells. ASN induced rapid and long-lasting calcium influx and activation of calciumdependent enzymes, including caspase-3, nitric oxide synthase and calpain. ASN-induced calpain activation leads to cleavage of Cdk5 activator p35, and subsequently to formation of p25 and Cdk5 overactivation. Moreover, we showed that exposure of PC12 cells to ASN increased Cdk5 activity by enhancement of its phosphorylation at Tyr15. Calpeptin, an inhibitor of calpains, and inhibitors of Cdk5, Roscovitine and BML-259, prevented ASN-evoked apoptosis and cell death, indicating the involvement of Cdk5 in mechanism of ASN toxicity. Our data showed that alterations in calcium homeostasis and modulation of calcium-dependent enzymes by extracellular ASN may contribute to the early stages of pathogenesis in Parkinson’s disease and other synucleinopathies.Supported by a grant from The National Science Centre 2012/05/B/NZ3/02047.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2013
• Tom: 73
• Numer: Suppl.1
• Opis fizyczny: p.23

Twórcy

autor

Adamczyk A.

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

autor

Gasowska M.

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

autor

Wilkaniec A.

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

autor

Cieslik M.

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

autor

Czapski G. A.

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