MicroRNAs: Meta-controllers of gene expression in synaptic activity emerge as genetic and diagnostic markers of human disease

University of Illinois, Department of Cell & Developmental Biology, Urbana, IL 61801, USA.
Pharmacology [?] Therapeutics (Impact Factor: 9.72). 04/2011; 130(1):26-37. DOI: 10.1016/j.pharmthera.2011.01.004
Source: PubMed


MicroRNAs are members of the non-protein-coding family of RNAs. They serve as regulators of gene expression by modulating the translation and/or stability of messenger RNA targets. The discovery of microRNAs has revolutionized the field of cell biology, and has permanently altered the prevailing view of a linear relationship between gene and protein expression. The increased complexity of gene regulation is both exciting and daunting, as emerging evidence supports a pervasive role for microRNAs in virtually every cellular process. This review briefly describes microRNA processing and formation of RNA-induced silencing complexes, with a focus on the role of RNA binding proteins in this process. We also discuss mechanisms for microRNA-mediated regulation of translation, particularly in dendritic spine formation and function, and the role of microRNAs in synaptic plasticity. We then discuss the evidence for altered microRNA function in cognitive brain disorders, and the effect of gene mutations revealed by single nucleotide polymorphism analysis on altered microRNA function and human disease. Further, we present evidence that altered microRNA expression in circulating fluids such as plasma/serum can correlate with, and serve as, novel diagnostic biomarkers of human disease.

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Available from: Julie Saugstad, Jul 10, 2014
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    • "However, it is still unclear exactly how HDACs are involved in cartilage degradation. MicroRNAs (miRNAs, miRs) have emerged as fine-tuning regulators for diverse biological processes [14] [15]. During their biogenesis, the miRNA genes are transcribed into primary miRNAs (pri-miR), which are processed by Drosha and Dicer to generate miRNA duplexes consisting of a mature and a passenger miR strand [16]. "
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    Biochimica et Biophysica Acta - Clinical 06/2015; 3(1):79-89. DOI:10.1016/j.bbacli.2014.11.009
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    • "miR-92a, miR-92a-1 * , miR-92a-2 * , and miR-92b are all members of the miR-92 family (also known as the miR-17 family) and were all up-regulated in mouse SN following chronic alcohol exposure (Most et al., unpublished results). miR-92b is involved in synaptic signaling (Ceman and Saugstad, 2011) and may be involved in the aberrant synaptic plasticity seen after alcohol exposure. In addition, miR-369 * is affected by alcohol. "
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    ABSTRACT: Local translation of mRNAs is a mechanism by which cells can rapidly remodel synaptic structure and function. There is ample evidence for a role of synaptic translation in the neuroadaptations resulting from chronic drug use and abuse. Persistent and coordinated changes of many mRNAs, globally and locally, may have a causal role in complex disorders such as addiction. In this review we examine the evidence that translational regulation by microRNAs drives synaptic remodeling and mRNA expression, which may regulate the transition from recreational to compulsive drug use. microRNAs are small, non-coding RNAs that control the translation of mRNAs in the cell and within spatially restricted sites such as the synapse. microRNAs typically repress the translation of mRNAs into protein by binding to the 3'UTR of their targets. As 'master regulators' of many mRNAs, changes in microRNAs could account for the systemic alterations in mRNA and protein expression observed with drug abuse and dependence. Recent studies indicate that manipulation of microRNAs affects addiction-related behaviors such as the rewarding properties of cocaine, cocaine-seeking behavior, and self-administration rates of alcohol. There is limited evidence, however, regarding how synaptic microRNAs control local mRNA translation during chronic drug exposure and how this contributes to the development of dependence. Here, we discuss research supporting microRNA regulation of local mRNA translation and how drugs of abuse may target this process. The ability of synaptic microRNAs to rapidly regulate mRNAs provides a discrete, localized system that could potentially be used as diagnostic and treatment tools for alcohol and other addiction disorders.
    Frontiers in Molecular Neuroscience 12/2014; 7:85. DOI:10.3389/fnmol.2014.00085 · 4.08 Impact Factor
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    • "In addition, miRNAs have a proven high chemical stability for repeated frozen-thaw cycles and long periods of storage (Chen et al., 2008) Moreover, the miRNA quantification in body fluids as disease biomarkers has been explored in different human diseases including certain types of cancers (Lawrie et al., 2008; Hu et al., 2010). Indeed, biochemical analysis of serum or plasma have been suggested as a potential and noninvasive source of biomarkers for diagnosis and monitoring of progression and treatment response for neurodegenerative disorders (Ceman and Saugstad, 2011). Here, we explore alterations at the expression level of serum miRNAs in PD patients and their potential use as disease biomarkers. "
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    ABSTRACT: Blood-cell-free circulating micro-RNAs (miRNAs) have been proposed as potential accessible biomarkers for neurodegenerative diseases such as Parkinson's disease (PD). Here we analyzed the serum levels of 377 miRNAs in a discovery set of 10 idiopathic Parkinson's disease (IPD) patients, 10 PD patients carriers of the LRRK2 G2019S mutation (LRRK2 PD), and 10 controls by using real-time quantitative PCR-based TaqMan MicroRNA arrays. We detected candidate differentially expressed miRNAs, which were further tested in a first validation set consisting of 20 IPD, 20 LRRK2 PD, and 20 control samples. We found four statistically significant miRNAs that were downregulated in either LRRK2 or IPD (miR-29a, miR-29c, miR-19a, and miR-19b). Subsequently, we validated these findings in a third set of samples consisting of 65 IPD and 65 controls and confirmed the association of downregulated levels of miR-29c, miR-29a, and miR-19b in IPD. Differentially expressed miRNAs are predicted to target genes belonging to pathways related to ECM–receptor interaction, focal adhesion, MAPK, Wnt, mTOR, adipocytokine, and neuron projection. Results from our exploratory study indicate that downregulated levels of specific circulating serum miRNAs are associated with PD and suggest their potential use as noninvasive biomarkers for PD. Future studies should further confirm the association of these miRNAs with PD. © 2014 Wiley Periodicals, Inc.
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