title: MicroRNA-7 protects against 1-methyl-4-phenylpyridinium-induced cell death by targeting RelA.
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.
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and.
authors.forename: Doo Chul
authors.initials: DC
authors.lastname: Choi
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and.
authors.forename: Yoon-Jee
authors.initials: YJ
authors.lastname: Chae
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and.
authors.forename: Savan
authors.initials: S
authors.lastname: Kabaria
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and.
authors.forename: Amrita Datta
authors.initials: AD
authors.lastname: Chaudhuri
authors.affiliation: Center for Advanced Proteomics Research, Rutgers New Jersey Medical School, Newark, New Jersey 07103.
authors.forename: Mohit Raja
authors.initials: MR
authors.lastname: Jain
authors.affiliation: Center for Advanced Proteomics Research, Rutgers New Jersey Medical School, Newark, New Jersey 07103.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and.
authors.forename: M Maral
authors.initials: MM
authors.lastname: Mouradian
authors.affiliation: Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, and junneu@rwjms.rutgers.edu.
authors.forename: Eunsung
authors.identifier: http://orcid.org/0000-0001-5694-2599
authors.initials: E
authors.lastname: Junn
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000378:metabolism*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000517:prevention & control*; D013378:Substantia Nigra / Q000378:metabolism; D051996:Transcription Factor RelA / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics
chemical_list: D015655:1-Methyl-4-phenylpyridinium; D035683:MicroRNAs; D016328:NF-kappa B; D018696:Neuroprotective Agents; D051996:Transcription Factor RelA; D051844:alpha-Synuclein; C549242:MIRN7-1 microRNA, human; C498143:RELA protein, human
keywords: MPP+; NF-κB; Parkinson's disease; RelA; cell death; microRNA-7