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

FEBS Lett. 2013 Sep 17;587(18):3135-41. doi: 10.1016/j.febslet.2013.07.053. Epub 2013 Aug 14.

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.

Keywords: Alpha-synuclein; Calpain; Cyclin-dependent kinase 5; Parkinson’s disease; Phosphorylation; p35.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Calcium / metabolism
  • Calpain / antagonists & inhibitors
  • Calpain / genetics*
  • Calpain / metabolism
  • Cyclin-Dependent Kinase 5 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 5 / genetics*
  • Cyclin-Dependent Kinase 5 / metabolism
  • Enzyme Activation / drug effects
  • Extracellular Space
  • Gene Expression Regulation
  • PC12 Cells
  • Phosphorylation
  • Phosphotransferases / genetics*
  • Phosphotransferases / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Signal Transduction
  • alpha-Synuclein / genetics*
  • alpha-Synuclein / metabolism
  • alpha-Synuclein / pharmacology

Substances

  • Cdk5r1 protein, rat
  • Protein Kinase Inhibitors
  • alpha-Synuclein
  • Phosphotransferases
  • Cyclin-Dependent Kinase 5
  • Cdk5 protein, rat
  • Calpain
  • Calcium