MicroRNA-7 protects against 1-methyl-4-phenylpyridinium-induced cell death by targeting RelA

Doo Chul Choi, Yoon Jee Chae, Savan Kabaria, Amrita Datta Chaudhuri, Mohit Raja Jain, Hong Li, M. Maral Mouradian, Eunsung Junn

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Mitochondrial complex I impairment in PD is modeled in vitro by the susceptibility of dopaminergic neurons to the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP). In the present study, we demonstrate that microRNA-7 (miR-7), which is expressed in tyrosine hydroxylase-positive nigral neurons in mice and humans, protects cells from MPP -induced toxicity in dopaminergic SH-SY5Y cells, differentiated human neural progenitor ReNcell VM cells, and primary mouse neurons. RelA, a component of nuclear factor-κB (NF-κB), was identified to be downregulated by miR-7 using quantitative proteomic analysis. Through a series of validation experiments, it was confirmed that RelA mRNA is a target of miR-7 and is required for cell death following MPP exposure. Further, RelA mediates MPP –induced suppression of NF-κB activity, which is essential for MPP -induced cell death. Accordingly, the protective effect of miR-7 is exerted through relieving NF-κB suppression by reducing RelA expression. These findings provide a novel mechanism by which NF-κB suppression, rather than activation, underlies the cell death mechanism following MPP toxicity, have implications for the pathogenesis of PD, and suggest miR-7 as a therapeutic target for this disease.

Original languageEnglish (US)
Pages (from-to)12725-12737
Number of pages13
JournalJournal of Neuroscience
Volume34
Issue number38
DOIs
StatePublished - Sep 17 2014

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

Keywords

  • Cell death
  • MPP
  • NF-κB
  • Parkinson’s disease
  • RelA
  • microRNA-7

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