Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity

Neuron. 2003 Mar 6;37(5):735-49. doi: 10.1016/s0896-6273(03)00084-9.

Abstract

Mutations in parkin, which encodes a RING domain protein associated with ubiquitin ligase activity, lead to autosomal recessive Parkinson's disease characterized by midbrain dopamine neuron loss. Here we show that parkin functions in a multiprotein ubiquitin ligase complex that includes the F-box/WD repeat protein hSel-10 and Cullin-1. HSel-10 serves to target the parkin ubiquitin ligase activity to cyclin E, an hSel-10-interacting protein previously implicated in the regulation of neuronal apoptosis. Consistent with the notion that cyclin E is a substrate of the parkin ubiquitin ligase complex, parkin deficiency potentiates the accumulation of cyclin E in cultured postmitotic neurons exposed to the glutamatergic excitotoxin kainate and promotes their apoptosis. Furthermore, parkin overexpression attenuates the accumulation of cyclin E in toxin-treated primary neurons, including midbrain dopamine neurons, and protects them from apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • HeLa Cells
  • Humans
  • Kainic Acid / toxicity*
  • Ligases / biosynthesis*
  • Ligases / genetics
  • Mice
  • Mitosis / drug effects*
  • Mitosis / physiology*
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Peptide Synthases / biosynthesis*
  • Peptide Synthases / genetics
  • SKP Cullin F-Box Protein Ligases
  • Ubiquitin-Protein Ligases*

Substances

  • SKP Cullin F-Box Protein Ligases
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Ligases
  • Peptide Synthases
  • Kainic Acid