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      Advances with microRNAs in Parkinson’s disease research

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          Abstract

          Parkinson’s disease (PD) is the second-most common age-dependent neurodegenerative disorder and is caused by severe degeneration of dopaminergic neurons in the substantia nigra pars compacta. Unfortunately, current treatment only targets symptoms and involves dopamine replacement therapy, which does not counteract progressive degeneration. MicroRNAs (miRNAs) are a class of small RNA molecules implicated in post-transcriptional regulation of gene expression during development. Recent studies show that miRNAs are playing an important role in the pathophysiology of PD. miRNA-based therapy is a powerful tool with which to study gene function, investigate the mechanism of the disease, and validate drug targets. In this review, we focus on the recent advances of the use of miRNAs in the pathogenesis of PD.

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          Most cited references 63

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          Targeting microRNAs in cancer: rationale, strategies and challenges.

          MicroRNAs (miRNAs) are evolutionarily conserved small non-coding RNAs that regulate gene expression. Early studies have shown that miRNA expression is deregulated in cancer and experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression. Based on these observations, miRNA-based anticancer therapies are being developed, either alone or in combination with current targeted therapies, with the goal to improve disease response and increase cure rates. The advantage of using miRNA approaches is based on its ability to concurrently target multiple effectors of pathways involved in cell differentiation, proliferation and survival. In this Review, we describe the role of miRNAs in tumorigenesis and critically discuss the rationale, the strategies and the challenges for the therapeutic targeting of miRNAs in cancer.
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            A MicroRNA feedback circuit in midbrain dopamine neurons.

            MicroRNAs (miRNAs) are evolutionarily conserved, 18- to 25-nucleotide, non-protein coding transcripts that posttranscriptionally regulate gene expression during development. miRNAs also occur in postmitotic cells, such as neurons in the mammalian central nervous system, but their function is less well characterized. We investigated the role of miRNAs in mammalian midbrain dopaminergic neurons (DNs). We identified a miRNA, miR-133b, that is specifically expressed in midbrain DNs and is deficient in midbrain tissue from patients with Parkinson's disease. miR-133b regulates the maturation and function of midbrain DNs within a negative feedback circuit that includes the paired-like homeodomain transcription factor Pitx3. We propose a role for this feedback circuit in the fine-tuning of dopaminergic behaviors such as locomotion.
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              RNA polymerase III transcribes human microRNAs.

              Prior work demonstrates that mammalian microRNA (miRNA or miR) expression requires RNA polymerase II (Pol II). However, the transcriptional requirements of many miRNAs remain untested. Our genomic analysis of miRNAs in the human chromosome 19 miRNA cluster (C19MC) revealed that they are interspersed among Alu repeats. Because Alu transcription occurs through RNA Pol III recruitment, and we found that Alu elements upstream of C19MC miRNAs retain sequences important for Pol III activity, we tested the promoter requirements of C19MC miRNAs. Chromatin immunoprecipitation and cell-free transcription assays showed that Pol III, but not Pol II, is associated with miRNA genomic sequence and sufficient for transcription. Moreover, the mature miRNA sequences of approximately 50 additional human miRNAs lie within Alu and other known repetitive elements. These findings extend the current view of miRNA origins and the transcriptional machinery driving their expression.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2013
                01 October 2013
                : 7
                : 1103-1113
                Affiliations
                [1 ]Department of Neurology, Xinhua Hospital Affiliated with Shanghai JiaoTong University School of Medicine, Shanghai, People’s Republic of China
                [2 ]School of Pharmacy, Shanghai JiaoTong University, Shanghai, People’s Republic of China
                [3 ]Research Institute of Micro/Nano Science and Technology, Shanghai JiaoTong University, Shanghai, People’s Republic of China
                Author notes

                *These authors contributed equally to this work

                Correspondence: Weien Yuan, School of Pharmacy, Shanghai JiaoTong University, 800 Dongchuan Road, Shanghai 200240, People’s Republic of China, Tel +86 21 3420 5072, Fax +86 21 3420 5072, Email yuanweien@ 123456126.com
                Zhenguo Liu, Department of Neurology, Xinhua Hospital Affiliated with Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, People’s Republic of China, Tel +86 21 2507 7501, Fax +86 21 2507 7501, Email zhenguoliu2004@ 123456aliyun.com
                Article
                dddt-7-1103
                10.2147/DDDT.S48500
                3792848
                © 2013 Ma et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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