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      Inhibition of miR-181a promotes midbrain neuronal growth through a Smad1/5-dependent mechanism: implications for Parkinson’s disease

      , 1 , 1 , 2 , , 1 , 2 , 3

      Neuronal Signaling

      Portland Press Ltd.

      axon, dopamine, microRNA

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          Abstract

          Parkinson’s disease (PD) is the second most common neurodegenerative disease, and is characterized by the progressive degeneration of nigrostriatal dopaminergic (DA) neurons. Current PD treatments are symptomatic, wear off over time and do not protect against DA neuronal loss. Finding a way to re-grow midbrain DA (mDA) neurons is a promising disease-modifying therapeutic strategy for PD. However, reliable biomarkers are required to allow such growth-promoting approaches to be applied early in the disease progression. miR-181a has been shown to be dysregulated in PD patients, and has been identified as a potential biomarker for PD. Despite studies demonstrating the enrichment of miR-181a in the brain, specifically in neurites of postmitotic neurons, the role of miR-181a in mDA neurons remains unknown. Herein, we used cell culture models of human mDA neurons to investigate a potential role for miR-181a in mDA neurons. We used a bioninformatics analysis to identify that miR-181a targets components of the bone morphogenetic protein (BMP) signalling pathway, including the transcription factors Smad1 and Smad5, which we find are expressed by rat mDA neurons and are required for BMP-induced neurite growth. We also found that inhibition of neuronal miR-181a, resulted in increased Smad signalling, and induced neurite growth in SH-SY5Y cells. Finally, using embryonic rat cultures, we demonstrated that miR-181a inhibition induces ventral midbrain (VM) and cortical neuronal growth. These data describe a new role for miR-181a in mDA neurons, and provide proof of principle that miR-181a dysresgulation in PD may alter the activation state of signalling pathways important for neuronal growth in neurons affected in PD.

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          Most cited references 56

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          MicroRNAs: small RNAs with a big role in gene regulation.

           Sai-Lin He,  G Hannon (2004)
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            Transcriptome-wide identification of RNA-binding protein and microRNA target sites by PAR-CLIP.

            RNA transcripts are subject to posttranscriptional gene regulation involving hundreds of RNA-binding proteins (RBPs) and microRNA-containing ribonucleoprotein complexes (miRNPs) expressed in a cell-type dependent fashion. We developed a cell-based crosslinking approach to determine at high resolution and transcriptome-wide the binding sites of cellular RBPs and miRNPs. The crosslinked sites are revealed by thymidine to cytidine transitions in the cDNAs prepared from immunopurified RNPs of 4-thiouridine-treated cells. We determined the binding sites and regulatory consequences for several intensely studied RBPs and miRNPs, including PUM2, QKI, IGF2BP1-3, AGO/EIF2C1-4 and TNRC6A-C. Our study revealed that these factors bind thousands of sites containing defined sequence motifs and have distinct preferences for exonic versus intronic or coding versus untranslated transcript regions. The precise mapping of binding sites across the transcriptome will be critical to the interpretation of the rapidly emerging data on genetic variation between individuals and how these variations contribute to complex genetic diseases. Copyright 2010 Elsevier Inc. All rights reserved.
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              WEB-based GEne SeT AnaLysis Toolkit (WebGestalt): update 2013

              Functional enrichment analysis is an essential task for the interpretation of gene lists derived from large-scale genetic, transcriptomic and proteomic studies. WebGestalt (WEB-based GEne SeT AnaLysis Toolkit) has become one of the popular software tools in this field since its publication in 2005. For the last 7 years, WebGestalt data holdings have grown substantially to satisfy the requirements of users from different research areas. The current version of WebGestalt supports 8 organisms and 201 gene identifiers from various databases and different technology platforms, making it directly available to the fast growing omics community. Meanwhile, by integrating functional categories derived from centrally and publicly curated databases as well as computational analyses, WebGestalt has significantly increased the coverage of functional categories in various biological contexts including Gene Ontology, pathway, network module, gene–phenotype association, gene–disease association, gene–drug association and chromosomal location, leading to a total of 78 612 functional categories. Finally, new interactive features, such as pathway map, hierarchical network visualization and phenotype ontology visualization have been added to WebGestalt to help users better understand the enrichment results. WebGestalt can be freely accessed through http://www.webgestalt.org or http://bioinfo.vanderbilt.edu/webgestalt/.
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                Author and article information

                Journal
                ppneurosig
                NS
                Neuronal Signal.
                Neuronal Signaling
                Neuronal Signal.
                Portland Press Ltd.
                2059-6553
                11 January 2018
                26 January 2018
                31 March 2018
                : 2
                : 1
                Affiliations
                [1 ]Department of Anatomy and Neuroscience and Cork Neuroscience Centre, Western Gateway Building, University College Cork (UCC), Cork, Ireland
                [2 ]APC Microbiome Institute, UCC, Cork, Ireland
                [3 ]INFANT Centre, Cork University Maternity Hospital and UCC, Cork, Ireland
                Author notes
                Correspondence: Gerard W. O’Keeffe ( g.okeeffe@ 123456ucc.ie ) or Shane V. Hegarty ( shane.hegarty@ 123456ucc.ie )
                [*]

                These authors contributed equally to this work.

                Article
                10.1042/NS20170181
                © 2018 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                Counts
                Pages: 12
                Product
                Self URI (journal page): http://www.neuronalsignaling.org/
                Categories
                Research Articles
                Research Article
                21
                46
                47

                Neurology, Molecular medicine, Molecular biology, Neurosciences

                microRNA, axon, dopamine

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