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

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

Author information

1
Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and.
2
Center for Advanced Proteomics Research, Rutgers New Jersey Medical School, Newark, New Jersey 07103.
3
Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and junneu@rwjms.rutgers.edu.

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.

KEYWORDS:

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

PMID:
25232110
PMCID:
PMC4166159
DOI:
10.1523/JNEUROSCI.0985-14.2014
[Indexed for MEDLINE]
Free PMC Article

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