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  • 1
    Publication Date: 2012-11-23
    Description: Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian target of rapamycin (mTOR) is strongly implicated in ASDs by means of upstream signalling; however, downstream regulatory mechanisms are ill-defined. Here we show that knockout of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2)-an eIF4E repressor downstream of mTOR-or eIF4E overexpression leads to increased translation of neuroligins, which are postsynaptic proteins that are causally linked to ASDs. Mice that have the gene encoding 4E-BP2 (Eif4ebp2) knocked out exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviours (that is, social interaction deficits, altered communication and repetitive/stereotyped behaviours). Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2, protein levels restores the normal excitation/inhibition ratio and rectifies the social behaviour deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133997/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133997/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gkogkas, Christos G -- Khoutorsky, Arkady -- Ran, Israeli -- Rampakakis, Emmanouil -- Nevarko, Tatiana -- Weatherill, Daniel B -- Vasuta, Cristina -- Yee, Stephanie -- Truitt, Morgan -- Dallaire, Paul -- Major, Francois -- Lasko, Paul -- Ruggero, Davide -- Nader, Karim -- Lacaille, Jean-Claude -- Sonenberg, Nahum -- MOP-10848/Canadian Institutes of Health Research/Canada -- MOP-114994/Canadian Institutes of Health Research/Canada -- MOP-44050/Canadian Institutes of Health Research/Canada -- MOP-93679/Canadian Institutes of Health Research/Canada -- R01 CA140456/CA/NCI NIH HHS/ -- R01 CA154916/CA/NCI NIH HHS/ -- R01 GM088813/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Jan 17;493(7432):371-7. doi: 10.1038/nature11628. Epub 2012 Nov 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry & Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23172145" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/*genetics/*physiopathology ; Cell Adhesion Molecules, Neuronal/genetics/metabolism ; Eukaryotic Initiation Factor-4E/antagonists & inhibitors/*metabolism ; Eukaryotic Initiation Factors/deficiency/genetics/metabolism ; Male ; Mice ; Mice, Knockout ; Phenotype ; *Protein Biosynthesis ; Synapses/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2012-10-09
    Description: The endoplasmic reticulum (ER) is the primary organelle for folding and maturation of secretory and transmembrane proteins. Inability to meet protein-folding demand leads to "ER stress," and activates IRE1alpha, an ER transmembrane kinase-endoribonuclease (RNase). IRE1alpha promotes adaptation through splicing Xbp1 mRNA or apoptosis through incompletely understood mechanisms. Here, we found that sustained IRE1alpha RNase activation caused rapid decay of select microRNAs (miRs -17, -34a, -96, and -125b) that normally repress translation of Caspase-2 mRNA, and thus sharply elevates protein levels of this initiator protease of the mitochondrial apoptotic pathway. In cell-free systems, recombinant IRE1alpha endonucleolytically cleaved microRNA precursors at sites distinct from DICER. Thus, IRE1alpha regulates translation of a proapoptotic protein through terminating microRNA biogenesis, and noncoding RNAs are part of the ER stress response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742121/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742121/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Upton, John-Paul -- Wang, Likun -- Han, Dan -- Wang, Eric S -- Huskey, Noelle E -- Lim, Lionel -- Truitt, Morgan -- McManus, Michael T -- Ruggero, Davide -- Goga, Andrei -- Papa, Feroz R -- Oakes, Scott A -- DK063720/DK/NIDDK NIH HHS/ -- DP2 OD001925/OD/NIH HHS/ -- DP2OD001925/OD/NIH HHS/ -- GM080783/GM/NIGMS NIH HHS/ -- P30 DK063720/DK/NIDDK NIH HHS/ -- R01 CA136577/CA/NCI NIH HHS/ -- R01 CA136717/CA/NCI NIH HHS/ -- R01 CA140456/CA/NCI NIH HHS/ -- R01 CA154916/CA/NCI NIH HHS/ -- R01 DK080955/DK/NIDDK NIH HHS/ -- R01 GM080783/GM/NIGMS NIH HHS/ -- R01CA136577/CA/NCI NIH HHS/ -- R01CA136717/CA/NCI NIH HHS/ -- R01CA140456/CA/NCI NIH HHS/ -- R01CA154916/CA/NCI NIH HHS/ -- R01DK080955/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 Nov 9;338(6108):818-22. doi: 10.1126/science.1226191. Epub 2012 Oct 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23042294" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions ; Animals ; Apoptosis ; Brefeldin A/pharmacology ; Caspase 2/*genetics/*metabolism ; Cell-Free System ; Cells, Cultured ; Cysteine Endopeptidases/*genetics/*metabolism ; Down-Regulation ; Endoplasmic Reticulum/metabolism ; *Endoplasmic Reticulum Stress ; Endoribonucleases/chemistry/genetics/*metabolism ; Enzyme Activation ; HEK293 Cells ; Humans ; Mice ; Mice, Knockout ; MicroRNAs/*metabolism ; Mutant Proteins ; Protein Biosynthesis ; Protein-Serine-Threonine Kinases/chemistry/genetics/*metabolism ; RNA Stability ; RNA, Messenger/genetics/metabolism ; Up-Regulation
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Analytical Biochemistry 85 (1978), S. 476-487 
    ISSN: 0003-2697
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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