Copy Number Variants in miR-138 as a Potential Risk Factor for Early-Onset Alzheimer’s Disease

Boscher, Emmanuelle; Husson, Thomas; Quenez, Olivier; Laquerrière, Annie; Marguet, Florent; Cassinari, Kévin; Wallon, David; Martinaud, Olivier; Charbonnier, Camille; Nicolas, Gaël; Deleuze, Jean‐François; Boland, Anne; Lathrop, Mark; Frébourg, Thierry; Campion, Dominique; Hébert, Sébastien S.; Rovelet‐Lecrux, Anne

doi:10.3233/jad-180940

Cited by 18 publications

(13 citation statements)

References 63 publications

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“…Both the MiR-138-1 and miR-138-2 clusters are responded in the entirely identical mature miRNA sequences, which are located on the chromosomes 3p21.33 and 16q13, correspondingly [30,31]. The dynamic modulation of miR-138 has been detected in the multiple kinds of disease mechanisms, for instance, type-2 diabetes, rheumatoid arthritis, early-onset Alzheimer's disease and cancers [32][33][34][35]. Moreover, miRNA-138-5p has been indicated as a reverse factor of ge tinib resistance by inhibiting GPR124 (G protein-coupled receptor 124) expression in NSCLC (nonsmall cell lung cancer) cells [36].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

Mou

Pan

et al. 2020

Preprint

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Background: Kinase inhibitor sorafenib is the first-line targeted drug for advanced hepatocellular carcinoma (HCC) patients. However, the appearance of anti-cancer agents’ resistance has limited its therapeutic effect. Methods: In this study, quantitative real-time PCR (qPCR) and Western Blot were utilized to detect the levels of PAK5 in HCC sorafenib-resistant cells and their parental cells. The biological functions of miR-138-1-3p and PAK5 in sorafenib-resistant cells and their parental cells were explored by cell viability assay, plate colony formation assay and flow cytometric analysis. The potential mechanisms of PAK5 were evaluated via co-immunoprecipitation (co-IP), immunofluorescence, dual luciferase reporter assay and chromatin immunoprecipitation (ChIP). The effects of miR-138-1-3p and PAK5 on HCC sorafenib chemoresistant characteristics were investigated by a xenotransplantation model. Results: We detected significant down-regulation of miR-138-1-3p and up-regulation of PAK5 in HCC sorafenib resistance cell lines. Mechanical studies revealed that miR-138-1-3p reduced the protein expression of PAK5 by directly targeting the 3′-UTR of PAK5 mRNA. In addition, we verified that PAK5 elevated the phosphorylation and nuclear translocation of β-catenin that enhanced the transcriptional activity of multidrug resistance protein ABCB1. Conclusions: PAK5 contributed to the sorafenib chemoresistant characteristics of HCC by activity β-catenin/ABCB1 signaling pathway. Our findings identified the correlation between miR-138-1-3p and PAK5 and the molecular mechanisms of PAK5-mediated HCC sorafenib resistance, which provided a potential therapeutic target for advanced HCC patients.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

Mou

Pan

et al. 2020

Preprint

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“…Based on the role of miR-138 in Aβ production and tau phosphorylation, this CNV might be implicated in the risk of EOAD (Boscher et al, 2019). Functionally, miR-138 upregulation enhances Aβ synthesis and tau phosphorylation through modulation of GSK-3β and FERMT2 (Boscher et al, 2019). Other studies have demonstrated the role of rs2910164 of pri-miR-146a, rs57095329 of miR-146a, and rs2291418 of miR-1229 precursor in conferring risk of AD (Table 4).…”

Section: Mirna Polymorphisms and Risk Of Admentioning

confidence: 99%

“…Duplication of the MIR138-2 locus has been one of these CNVs. Based on the role of miR-138 in Aβ production and tau phosphorylation, this CNV might be implicated in the risk of EOAD (Boscher et al, 2019). Functionally, miR-138 upregulation enhances Aβ synthesis and tau phosphorylation through modulation of GSK-3β and FERMT2 (Boscher et al, 2019).…”

Section: Mirna Polymorphisms and Risk Of Admentioning

confidence: 99%

The Eminent Role of microRNAs in the Pathogenesis of Alzheimer's Disease

Samadian

Gholipour

Hajiesmaeili

et al. 2021

Front. Aging Neurosci.

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Alzheimer's disease (AD) is an irrevocable neurodegenerative condition characterized by the presence of senile plaques comprising amassed β-amyloid peptides (Aβ) and neurofibrillary tangles mainly comprising extremely phosphorylated Tau proteins. Recent studies have emphasized the role of microRNAs (miRNAs) in the development of AD. A number of miRNAs, namely, miR-200a-3p, miR-195, miR-338-5p, miR-34a-5p, miR-125b-5p, miR-132, miR-384, miR-339-5p, miR-135b, miR-425-5p, and miR-339-5p, have been shown to participate in the development of AD through interacting with BACE1. Other miRNAs might affect the inflammatory responses in the course of AD. Aberrant expression of several miRNAs in the plasma samples of AD subjects has been shown to have the aptitude for differentiation of AD subjects from healthy subjects. Finally, a number of AD-modifying agents affect miRNA profile in cell cultures or animal models. We have performed a comprehensive search and summarized the obtained data about the function of miRNAs in AD in the current review article.

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“…MiR-132 has been implicated in synaptic plasticity together with miR-134 and miR-138 (Bicker et al, 2014). Duplication of the miR-138-2 locus was observed exclusively in early onset AD cases and miR-138 overexpression in vitro induced Aβ production and tau phosphorylation (Boscher et al, 2019). Interestingly, levels of miR-132 and miR-138-2 were significantly decreased in aged Tg4-42 mice indicating that dendritic mRNA transport and local translation in the postsynaptic compartment play an important role in synaptic plasticity, learning and memory (Bicker et al, 2014) in this model system for AD.…”

Section: Mirs Identified In the Hippocampus Of 8 Month Old Tg4-42 Micementioning

confidence: 99%

miRNA Alterations Elicit Pathways Involved in Memory Decline and Synaptic Function in the Hippocampus of Aged Tg4-42 Mice

et al. 2020

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The transcriptome of non-coding RNA (ncRNA) species is increasingly focused in Alzheimer's disease (AD) research. NcRNAs comprise, among others, transfer RNAs, long non-coding RNAs and microRNAs (miRs), each with their own specific biological function. We used smallRNASeq to assess miR expression in the hippocampus of young (3 month old) and aged (8 month old) Tg4-42 mice, a model system for sporadic AD, as well as age-matched wildtype controls. Tg4-42 mice express N-truncated Aβ 4-42 , develop age-related neuron loss, reduced neurogenesis and behavioral deficits. Our results do not only confirm known miR-AD associations in Tg4-42 mice, but more importantly pinpoint 22 additional miRs associated to the disease. Twenty-five miRs were differentially expressed in both aged Tg4-42 and aged wildtype mice while eight miRs were differentially expressed only in aged wildtype mice, and 33 only in aged Tg4-42 mice. No significant alteration in the miRNome was detected in young mice, which indicates that the changes observed in aged mice are downstream effects of Aβ-induced pathology in the Tg4-42 mouse model for AD. Targets of those miRs were predicted using miRWalk. For miRs that were differentially expressed only in the Tg4-42 model, 128 targets could be identified, whereas 18 genes were targeted by miRs only differentially expressed in wildtype mice and 85 genes were targeted by miRs differentially expressed in both mouse models. Genes targeted by differentially expressed miRs in the Tg4-42 model were enriched for negative regulation of longterm synaptic potentiation, learning or memory, regulation of trans-synaptic signaling and modulation of chemical synaptic transmission obtained. This untargeted miR sequencing approach supports previous reports on the Tg4-42 mice as a valuable model for AD. Furthermore, it revealed miRs involved in AD, which can serve as biomarkers or therapeutic targets.

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Copy Number Variants in miR-138 as a Potential Risk Factor for Early-Onset Alzheimer’s Disease

Cited by 18 publications

References 63 publications

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

MicroRNA-138-1-3p sensitizes sorafenib to hepatocellular carcinoma by targeting PAK5 mediated β-catenin/ABCB1 signaling pathway

The Eminent Role of microRNAs in the Pathogenesis of Alzheimer's Disease

miRNA Alterations Elicit Pathways Involved in Memory Decline and Synaptic Function in the Hippocampus of Aged Tg4-42 Mice

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