Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease

Nat Cell Biol. 2011 May;13(5):568-79. doi: 10.1038/ncb2217. Epub 2011 Apr 17.

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is increasingly implicated in various neurodegenerative diseases. Deregulated Cdk5 activity has been associated with neuronal death, but the underlying mechanisms are not well understood. Here we report an unexpected role for Cdk5 in the regulation of induced autophagy in neurons. We have identified endophilin B1 (EndoB1) as a Cdk5 substrate, and show that Cdk5-mediated phosphorylation of EndoB1 is required for autophagy induction in starved neurons. Furthermore, phosphorylation of EndoB1 facilitates EndoB1 dimerization and recruitment of UVRAG (UV radiation resistance-associated gene). More importantly, Cdk5-mediated phosphorylation of EndoB1 is essential for autophagy induction and neuronal loss in models of Parkinson's disease. Our findings not only establish Cdk5 as a critical regulator of autophagy induction, but also reveal a role for Cdk5 and EndoB1 in the pathophysiology of Parkinson's disease through modulating autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / metabolism*
  • Animals
  • Autophagy*
  • Cyclin-Dependent Kinase 5 / chemistry
  • Cyclin-Dependent Kinase 5 / metabolism*
  • Disease Models, Animal*
  • Mice
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology*
  • Phosphorylation
  • Protein Binding

Substances

  • Acyltransferases
  • 2-acylglycerophosphate acyltransferase
  • Cyclin-Dependent Kinase 5
  • Cdk5 protein, mouse