Genetic iron chelation protects against proteasome inhibition-induced dopamine neuron degeneration

Wen Zhu, Xuping Li, Wenjie Xie, Feifei Luo, Deepinder Kaur, Julie K. Andersen, Joseph Jankovic, Weidong Le

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Impairment of the ubiquitin proteasome system (UPS) and iron accumulation in the substantia nigra (SN) have both been implicated in the pathogenesis of Parkinson's disease (PD). We previously reported that chemical iron chelation can protect against proteasome inhibitor lactacystin-induced dopamine (DA) neurodegeneration in vivo. Here, we tested potential neuroprotection via genetic expression of the iron chelator human ferritin heavy chain (H-ferritin). We found that overexpression of H-ferritin in DA neurons significantly reduced lactacystin-induced nigral DA neuron loss and striatal DA depletion. Overexpression of H-ferritin also attenuated elevated levels of total and ferrous iron as well as the divalent metal ion transporter 1 (DMT1) in the SN following lactacystin treatment. In addition, overexpression of H-ferritin alleviated the inhibitory effects of lactacystin on proteasome activity in the nigral tissues. These results suggest that H-ferritin exerts neuroprotection possibly by modulating iron homeostasis and restoring proteasome activity.

Original languageEnglish (US)
Pages (from-to)307-313
Number of pages7
JournalNeurobiology of Disease
Volume37
Issue number2
DOIs
StatePublished - Feb 1 2010

Keywords

  • DMT1
  • Ferritin
  • Iron chelation
  • Parkinson's disease
  • UPS impairment

ASJC Scopus subject areas

  • Neurology

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