S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function

Science. 2004 May 28;304(5675):1328-31. doi: 10.1126/science.1093891. Epub 2004 Apr 22.

Abstract

Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alzheimer Disease / metabolism
  • Animals
  • Brain / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Catalytic Domain
  • Cell Death
  • Cell Line
  • Cysteine Proteinase Inhibitors / pharmacology
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lewy Body Disease / metabolism
  • MPTP Poisoning / metabolism
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nitric Oxide / metabolism*
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Parkinson Disease / metabolism*
  • Recombinant Proteins / metabolism
  • Synucleins
  • Transfection
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / antagonists & inhibitors
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Carrier Proteins
  • Cysteine Proteinase Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Nitric Oxide Donors
  • Recombinant Proteins
  • SNCAIP protein, human
  • Sncaip protein, mouse
  • Synucleins
  • Ubiquitin
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Ubiquitin-Protein Ligases
  • parkin protein