Stress-induced phospho-ubiquitin formation causes parkin degradation

Sci Rep. 2019 Aug 12;9(1):11682. doi: 10.1038/s41598-019-47952-5.

Abstract

Mutations in the E3 ubiquitin ligase parkin are the most common known cause of autosomal recessive Parkinson's disease (PD), and parkin depletion may play a role in sporadic PD. Here, we sought to elucidate the mechanisms by which stress decreases parkin protein levels using cultured neuronal cells and the PD-relevant stressor, L-DOPA. We find that L-DOPA causes parkin loss through both oxidative stress-independent and oxidative stress-dependent pathways. Characterization of the latter reveals that it requires both the kinase PINK1 and parkin's interaction with phosphorylated ubiquitin (phospho-Ub) and is mediated by proteasomal degradation. Surprisingly, autoubiquitination and mitophagy do not appear to be required for such loss. In response to stress induced by hydrogen peroxide or CCCP, parkin degradation also requires its association with phospho-Ub, indicating that this mechanism is broadly generalizable. As oxidative stress, metabolic dysfunction and phospho-Ub levels are all elevated in PD, we suggest that these changes may contribute to a loss of parkin expression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone / analogs & derivatives
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone / pharmacology
  • Cell Differentiation
  • Cell Line, Tumor
  • Embryo, Mammalian
  • Gene Expression Regulation
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Levodopa / pharmacology*
  • Models, Biological
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / pathology
  • PC12 Cells
  • Parkinsonian Disorders / genetics
  • Parkinsonian Disorders / metabolism
  • Parkinsonian Disorders / pathology
  • Phosphorylation / drug effects
  • Primary Cell Culture
  • Proteasome Endopeptidase Complex / drug effects
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Kinases / genetics*
  • Protein Kinases / metabolism
  • Proteolysis
  • Rats
  • Ubiquitin / genetics*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Ubiquitin
  • Levodopa
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Hydrogen Peroxide
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase
  • Proteasome Endopeptidase Complex