Dataset Information

Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153.

ABSTRACT: Genetic and biochemical studies have established a central role for alpha-synuclein accumulation in the pathogenesis of Parkinson disease. Here, two microRNAs, namely mir-7 and mir-153, have been identified to regulate alpha-synuclein levels post-transcriptionally. These microRNAs bind specifically to the 3'-untranslated region of alpha-synuclein and down-regulate its mRNA and protein levels, with their effect being additive. They are expressed predominantly in the brain with a pattern that mirrors synuclein expression in different tissues as well as during neuronal development, indicating that they play a tuning role in the amount of alpha-synuclein produced. Overexpression of mir-7 and mir-153 significantly reduces endogenous alpha-synuclein levels, whereas inhibition of mir-7 and mir-153 enhances translation of a luciferase construct bearing the alpha-synuclein 3'-untranslated region in primary neurons. These findings reveal a significant additional mechanism by which alpha-synuclein is regulated and point toward new therapeutic regimes for lowering endogenous alpha-synuclein levels in patients with familial or sporadic Parkinson disease.

SUBMITTER: Doxakis E

PROVIDER: S-EPMC2857101 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153.

Doxakis Epaminondas E

The Journal of biological chemistry 20100127 17

Genetic and biochemical studies have established a central role for alpha-synuclein accumulation in the pathogenesis of Parkinson disease. Here, two microRNAs, namely mir-7 and mir-153, have been identified to regulate alpha-synuclein levels post-transcriptionally. These microRNAs bind specifically to the 3'-untranslated region of alpha-synuclein and down-regulate its mRNA and protein levels, with their effect being additive. They are expressed predominantly in the brain with a pattern that mirr ...[more]

PMID: 20106983

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Project description:?-Synuclein is a member of the synucleins family of small proteins, which consists of three members:?, ?- and ?-synuclein. ?-Synuclein is abnormally expressed in a high percentage of advanced and metastatic tumors, but not in normal or benign tissues. Furthermore, ?-synuclein expression is strongly correlated with disease progression, and can stimulate proliferation, induce invasion and metastasis of cancer cells. ?-Synuclein transcription is regulated basically through the binding of AP-1 to specific sequences in intron 1. Here we show that ?-synuclein expression may be also regulated by micro RNAs (miRs) on post-transcriptional level. According to prediction by several methods, the 3'-untranslated region (UTR) of ?-synuclein gene contains targets for miRs. Insertion of ?-synuclein 3'-UTR downstream of the reporter luciferase (LUC) gene causes a 51% reduction of LUC activity after transfection into SKBR3 and Y79 cells, confirming the presence of efficient targets for miRs in this fragment. Expression of miR-4437 and miR-4674 for which putative targets in 3'-UTR were predicted caused a 61.2% and 60.1% reduction of endogenous ?-synuclein expression confirming their role in gene expression regulation. On the other hand, in cells overexpressing ?-synuclein no significant effect of miRs on ?-synuclein expression was found suggesting that miRs exert their regulatory effect only at low or moderate, but not at high level of ?-synuclein expression. Elevated level of ?-synuclein differentially changes the level of several miRs expression, upregulating the level of some miRs and downregulating the level of others. Three miRs upregulated as a result of ?-synuclein overexpression, i.e., miR-885-3p, miR-138 and miR-497 have putative targets in 3'-UTR of the ?-synuclein gene. Some of miRs differentially regulated by ?-synuclein may modulate signaling pathways and cancer related gene expression. This study demonstrates that miRs might provide cell-specific regulation of ?-synuclein expression and set the stage to further evaluate their role in pathophysiological processes.

Dataset Information

Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153.

Publications

Post-transcriptional regulation of alpha-synuclein expression by mir-7 and mir-153.

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