Rademakers, R. et al. Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum. Mol. Genet. 17, 3631-3642

Department of Neuroscience, Mayo Clinic, Jacksonville, FL FL 32224, USA.
Human Molecular Genetics (Impact Factor: 6.39). 09/2008; 17(23):3631-42. DOI: 10.1093/hmg/ddn257
Source: PubMed


Loss-of-function mutations in progranulin (GRN) cause ubiquitin- and TAR DNA-binding protein 43 (TDP-43)-positive frontotemporal dementia (FTLD-U), a progressive neurodegenerative disease affecting approximately 10% of early-onset dementia patients. Here we expand the role of GRN in FTLD-U and demonstrate that a common genetic variant (rs5848), located in the 3'-untranslated region (UTR) of GRN in a binding-site for miR-659, is a major susceptibility factor for FTLD-U. In a series of pathologically confirmed FTLD-U patients without GRN mutations, we show that carriers homozygous for the T-allele of rs5848 have a 3.2-fold increased risk to develop FTLD-U compared with homozygous C-allele carriers (95% CI: 1.50-6.73). We further demonstrate that miR-659 can regulate GRN expression in vitro, with miR-659 binding more efficiently to the high risk T-allele of rs5848 resulting in augmented translational inhibition of GRN. A significant reduction in GRN protein was observed in homozygous T-allele carriers in vivo, through biochemical and immunohistochemical methods, mimicking the effect of heterozygous loss-of-function GRN mutations. In support of these findings, the neuropathology of homozygous rs5848 T-allele carriers frequently resembled the pathological FTLD-U subtype of GRN mutation carriers. We suggest that the expression of GRN is regulated by miRNAs and that common genetic variability in a miRNA binding-site can significantly increase the risk for FTLD-U. Translational regulation by miRNAs may represent a common mechanism underlying complex neurodegenerative disorders.

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    • "downofGRNshowedare-localizationofTDP-43inthecyto- plasm(Guoetal.,2010). Throughgeneticassociationanalysis,acommongeneticvari- ationlocalizedonthe3′UTRofGRN(rs5848)wasshownto representageneticriskfactorforFTD(Rademakersetal.,2008). Progranulinlevelsinbrainextractsfromrs5848TThomozy- gousFTDpatientswerelowerthaninCCcarriers,asobserved throughwesternblotanalyses,ELISA,andimmunohistochemistry .AstrongerbindingofmiR-659inthe3′UTRofGRNwas showninthepresenceofthers5848Tvariant,andmightexplain thereducedprogranulinlevels. "
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    ABSTRACT: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by degeneration of the fronto temporal lobes and abnormal protein inclusions. It exhibits a broad clinicopathological spectrum and has been linked to mutations in seven different genes. We will provide a picture, which connects the products of these genes, albeit diverse in nature and function, in a network. Despite the paucity of information available for some of these genes, we believe that RNA processing and post-transcriptional regulation of gene expression might constitute a common theme in the network. Recent studies have unraveled the role of mutations affecting the functions of RNA binding proteins and regulation of microRNAs. This review will combine all the recent findings on genes involved in the pathogenesis of FTD, highlighting the importance of a common network of interactions in order to study and decipher the heterogeneous clinical manifestations associated with FTD. This approach could be helpful for the research of potential therapeutic strategies.
    Frontiers in Molecular Neuroscience 03/2015; 8:9. DOI:10.3389/fnmol.2015.00009 · 4.08 Impact Factor
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    • "For instance, the Parkinson’s disease-associated rs12720208 SNP is located in the miR-433 target site of Fibroblast growth factor 20, and affects miRNA-mediated repression (Wang et al., 2008). The rs5848 SNP, associated with TDP43-positive frontotemporal dementias, is located in the miR-659 target site of the Progranulin gene, also affecting the miRNA-mediated repression (Rademakers et al., 2008). Previously, we have shown that AD-associated SNPs present in the untranslated region (3′UTR) of APP could directly affect miRNA function (Delay et al., 2011). "
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    ABSTRACT: Despite the growing number of genome-wide association studies, the involvement of polymorphisms in microRNA target sites (polymiRTS) in Alzheimer's disease (AD) remains poorly investigated. Recently, we have shown that AD-associated single-nucleotide polymorphisms (SNPs) present in the 3' untranslated region (3'UTR) of amyloid precursor protein (APP) could directly affect miRNA function. In theory, loss of microRNA (miRNA) function could lead to risk for AD by increasing APP expression and Aβ peptide production. In this study, we tested the hypothesis that Nicastrin, a γ-secretase subunit involved in Aβ generation, could be regulated by miRNAs, and consequently affected by 3'UTR polymorphisms. Bioinformatic analysis identified 22 putative miRNA binding sites located in or near Nicastrin 3'UTR polymorphisms. From these miRNA candidates, six were previously shown to be expressed in human brain. We identified miR-24, miR-186, and miR-455 as regulators of Nicastrin expression, both in vitro and under physiological conditions in human cells, which resulted in altered Aβ secretion. Using luciferase-based assays, we further demonstrated that rs113810300 and rs141849450 SNPs affected miRNA-mediated repression of Nicastrin. Notably, rs141849450 completely abolished the miR-455-mediated repression of Nicastrin. Finally, the rs141849450 variant was identified in 1 out of 511 AD cases but not in 631 controls. These observations set the stage for future studies exploring the role of miRNAs and 3'UTR polymorphisms in AD.
    Frontiers in Molecular Neuroscience 07/2014; 7:67. DOI:10.3389/fnmol.2014.00067 · 4.08 Impact Factor
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    • "Evidence in this field is available also for neurodegenerative diseases: a study conducted on FTLD with TDP-43 inclusions (FTLD-TDP) by Rademakers et al. (2008) unveiled a functional effect for the high-risk allele of rs5848 in progranulin gene (GRN), which promotes a more efficient binding of miR-659, resulting in augmented translational inhibition of GRN. Similarly, rs1050283 in the oxidized LDL receptor 1 gene (OLR1), which acts as a risk factor for sporadic AD, was hypothesized to influence miR369-3p binding (Serpente et al., 2011). "
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    ABSTRACT: microRNAs (miRNAs) are small non-coding RNAs (20-22 nucleotides) playing a major role in post-transcriptional regulation of gene expression. miRNAs are predicted to regulate more than 50% of all the protein-coding genes. Increasing evidence indicates that they may play key roles in the biological pathways that regulate neurogenesis and synaptic plasticity, as well as in neurotransmitter homeostasis in the adult brain. In this article we review recent studies suggesting that miRNAs may be involved in the pathophysiology of neuropsychiatric disorders and in the action of psychotropic drugs, in particular by analyzing the contribution of genomic studies in patients' peripheral tissues. Alterations in miRNA expression have been observed in schizophrenia, bipolar disorder, major depression, Parkinson's disease, Alzheimer's disease and other neuropsychiatric conditions. In particular, intriguing findings concern the identification of disease-associated miRNA signatures in peripheral tissues, or modifications in miRNA profiles induced by drug treatments. Furthermore, genetic variations in miRNA sequences and miRNA-related genes have been described in neuropsychiatric diseases. Overall, though still at a preliminary stage, several lines of evidence indicate an involvement of miRNAs in both the pathophysiology and pharmacotherapy of neuropsychiatric disorders. In this regard, the data obtained in peripheral tissues may provide further insights into the etiopathogenesis of several brain diseases and contribute to identify new biomarkers for diagnostic assessment improvement and treatment personalization.
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