Nurr1 deficiency predisposes to lactacystin-induced dopaminergic neuron injury in vitro and in vivo

Tianhong Pan, Wen Zhu, Hongru Zhao, Hao Deng, Wenjie Xie, Joseph Jankovic, Weidong Le

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Parkinson's disease (PD) has been proposed to result from a combination of genetic susceptibility and environmental exposure. Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in neuron degeneration and in pathogenesis of PD. Nurr1, a member of nuclear receptor superfamily, is a potential susceptibility gene for PD. In this in vitro and in vivo study, we investigated whether Nurr1 deficiency may predispose to environmental proteasome inhibitors-induced neuron injury. We found that lactacystin, an irreversible proteasome inhibitor, caused greater injury to SH-SY5Y cells that Nurr1 expression has been suppressed by small interference RNA (siRNA). On the contrary, the Nurr1 overexpressed SH-SY5Y cells by Nurr1 expression vector transfection rescued the lactacystin-induced injury. In vivo, stereotactic microinjection with lactacystin into right median forebrain bundle (MFB) of mice caused significant inhibition of the proteasome activity in both Nurr1 knock out heterozygous (Nurr1 +/-) mice and their littermate wild-type (Nurr1 +/+) mice. At same time, we found that there was a severer loss of tyrosine hydroxylase (TH)-positive neurons in substantia nigra (SN) and greater reduction of striatal dopamine (DA) levels in Nurr1 +/- mice as compared with that in Nurr1 +/+ mice. Furthermore, lactacystin-induced increase of cleaved PARP, cleaved caspase3 and p53 and decrease of bcl-2 in SN was significantly enhanced in Nurr1 +/- mice. These findings suggest that reduction in Nurr1 expression increases susceptibility to DAergic neuron injury induced by UPS impairment.

Original languageEnglish (US)
Pages (from-to)222-229
Number of pages8
JournalBrain Research
Volume1222
DOIs
StatePublished - Jul 30 2008

Keywords

  • Lactacystin
  • Nurr1
  • Parkinson's disease
  • SH-SY5Y cell
  • Ubiquitin-proteasome system

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

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