A mechanistic study of proteasome inhibition-induced iron misregulation in dopamine neuron degeneration

Xuping Li, Wen Jie Xie, Zhen Zhang, Sagar Kansara, Joseph Jankovic, Weidong Le

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Ubiquitin proteasome system (UPS) impairment and iron misregulation have been implicated in dopamine (DA) neuron degeneration in Parkinson's disease. As previously shown, proteasome inhibition in a rodent model can cause nigral neuron degeneration accompanied by iron accumulation. To investigate the involvement of iron in DA neuron degeneration, we generated an in vitro model by applying proteasome inhibitor lactacystin in DAergic cell line MES23.5 culture. We found that lactacystin caused marked increase in labile iron, reactive oxygen species and ubiquitin-conjugated protein aggregation prior to cell injury. These effects were attenuated by iron chelators or antioxidants. Furthermore, we demonstrated that the iron regulatory protein (IRP)/iron response element system contributed to UPS impairment-mediated DA neuron injury. We documented that IRP2 disruption resulted in an increase in transferrin receptor 1 (TfR1), a decrease in ferritin heavy chain (H-Frt), and eventually cell death. These findings provide insight into the mechanistic interplay between UPS impairment and iron misregulation and suggest that the disturbances in IRP2, TfR1 and H-Frt may contribute to DA neuron degeneration.

Original languageEnglish (US)
Pages (from-to)223-236
Number of pages14
JournalNeuroSignals
Volume20
Issue number4
DOIs
StatePublished - Nov 2012

Keywords

  • Dopamine neurodegeneration
  • Iron misregulation
  • Reactive oxygen species
  • Ubiquitin proteasome system

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Developmental Neuroscience

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