title: Extracellular alpha-synuclein induces calpain-dependent overactivation of cyclin-dependent kinase 5 in vitro.
abstract: Extracellular alpha-synuclein (ASN) could be involved in the pathomechanism of Parkinson's disease (PD) via disturbances of calcium homeostasis, activation of nitric oxide synthase and oxidative/nitrosative stress. In this study we analyzed the role of cyclin-dependent kinase 5 (Cdk5) in the molecular mechanism(s) of ASN toxicity. We found that exposure of PC12 cells to ASN increases Cdk5 activity via calpain-dependent p25 formation and by enhancement of Cdk5 phosphorylation at Tyr15. Cdk5 and calpain inhibitors prevented ASN-evoked cell death. Our findings, indicating the participation of Cdk5 in ASN toxicity, provide new insight into how extracellular ASN may trigger dopaminergic cell dysfunction in PD.
authors: Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland. gczapski@imdik.pan.pl
authors: Grzegorz A
authors: GA
authors: Czapski
authors: Magdalena
authors: M
authors: Gąssowska
authors: Anna
authors: A
authors: Wilkaniec
authors: Magdalena
authors: M
authors: Cieślik
authors: Agata
authors: A
authors: Adamczyk
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space; D005786:Gene Expression Regulation; D016716:PC12 Cells; D010766:Phosphorylation; D010770:Phosphotransferases / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C492235:Cdk5r1 protein, rat; D047428:Protein Kinase Inhibitors; D051844:alpha-Synuclein; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D002154:Calpain; D002118:Calcium
keywords: Alpha-synuclein; Calpain; Cyclin-dependent kinase 5; Parkinson’s disease; Phosphorylation; p35