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

J Neurosci. 2014 Sep 17;34(38):12725-37. doi: 10.1523/JNEUROSCI.0985-14.2014.


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.

Keywords: MPP+; NF-κB; Parkinson's disease; RelA; cell death; microRNA-7.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenylpyridinium / antagonists & inhibitors*
  • 1-Methyl-4-phenylpyridinium / toxicity
  • Animals
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cells, Cultured
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / physiology
  • Down-Regulation
  • Humans
  • Mice
  • MicroRNAs / biosynthesis
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • NF-kappa B / biosynthesis
  • Neurons / drug effects
  • Neuroprotective Agents / metabolism*
  • Parkinson Disease, Secondary / chemically induced
  • Parkinson Disease, Secondary / prevention & control*
  • Substantia Nigra / metabolism
  • Transcription Factor RelA / biosynthesis*
  • Transcription Factor RelA / genetics
  • Transfection
  • alpha-Synuclein / genetics


  • MIRN7 microRNA, human
  • MicroRNAs
  • NF-kappa B
  • Neuroprotective Agents
  • RELA protein, human
  • Transcription Factor RelA
  • alpha-Synuclein
  • 1-Methyl-4-phenylpyridinium