Mitochondrial Ros-Mediated Post-Transcriptional Regulation Of Α-Synuclein Through Mir-7 And Mir-153

Keywords

3′-UTR; microRNA; Mitochondria; Parkinson's disease; α-synuclein

Abstract

Dysregulation of human alpha-synuclein (α-SYN) is one of the major contributors in the pathogenesis of Parkinson's disease. 1-methyl-4-phenylpyridinium (MPP+) is well known neurotoxin which increases α-SYN expression and causes dopaminergic neuronal death. Increasing evidence suggests microRNAs (miRNAs), especially miRNA-7 and miR-153, have important role in the regulation of α-SYN translation and they can prevent MPP+-mediated neuronal death. Here, we examined whether MPP+-mediated upregulation of α-SYN expression is directly related to miRNA-7 and miR-153. First, we established HEK293/TR cells stably expressing both miR-7 and miR-153. Human α-SYN 3′-UTR containing target sites for both miRNAs was cloned next to a luciferase reporter construct. To control the total levels of reporter mRNA, a tetracycline-inducible system was used. Compared to wild-type HEK293/TR cells, cells overexpressing both miRNAs demonstrated about 75% reduction in luciferase activity. MPP+ treatment, however, significantly increased luciferase activity of human α-SYN 3′-UTR. Either quenching mitochondrial reactive oxygen species (ROS) or translational inhibition significantly reduced MPP+-mediated luciferase activity, suggesting mitochondrial ROS is responsible for MPP+-induced α-SYN translation. Together, our results suggest that MPP+-mediated increased α-SYN levels are contributed by mitochondrial ROS-mediated de novo protein synthesis which is regulated by miRNA-7 and miR-153.

Publication Date

11-20-2017

Publication Title

Neuroscience Letters

Volume

661

Number of Pages

132-136

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1016/j.neulet.2017.09.065

Socpus ID

85030760690 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85030760690

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