{"data":{"id":"10.6084/m9.figshare.1291145.v1","type":"dois","attributes":{"doi":"10.6084/m9.figshare.1291145.v1","prefix":"10.6084","suffix":"m9.figshare.1291145.v1","identifiers":[],"alternateIdentifiers":[],"creators":[{"name":"Costessi, Luisa","nameType":"Personal","givenName":"Luisa","familyName":"Costessi","affiliation":[],"nameIdentifiers":[]},{"name":"Porro, Fabiola","nameType":"Personal","givenName":"Fabiola","familyName":"Porro","affiliation":[],"nameIdentifiers":[]},{"name":"Iaconcig, Alessandra","nameType":"Personal","givenName":"Alessandra","familyName":"Iaconcig","affiliation":[],"nameIdentifiers":[]},{"name":"Muro, Andrés F","nameType":"Personal","givenName":"Andrés F","familyName":"Muro","affiliation":[],"nameIdentifiers":[]}],"titles":[{"title":"TDP-43 regulates β-adducin (Add2) transcript stability"}],"publisher":"Taylor \u0026 Francis","container":{},"publicationYear":2014,"subjects":[{"subject":"111714 Mental Health","subjectScheme":"FOR"},{"subject":"FOS: Health sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Health sciences","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Computational Biology"},{"subject":"110309 Infectious Diseases","subjectScheme":"FOR"},{"subject":"Hematology"},{"subject":"Biological Sciences"},{"subject":"Neuroscience"},{"subject":"Molecular Biology"},{"subject":"Genetics"},{"subject":"FOS: Biological sciences","schemeUri":"http://www.oecd.org/science/inno/38235147.pdf","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"FOS: Biological sciences","subjectScheme":"Fields of Science and Technology (FOS)"},{"subject":"Cell Biology"},{"subject":"Biochemistry"}],"contributors":[],"dates":[{"date":"2014-10-03","dateType":"Created"},{"date":"2016-01-19","dateType":"Updated"},{"date":"2014","dateType":"Issued"}],"language":null,"types":{"ris":"DATA","bibtex":"misc","citeproc":"dataset","schemaOrg":"Dataset","resourceType":"Dataset","resourceTypeGeneral":"Dataset"},"relatedIdentifiers":[{"relationType":"IsSupplementTo","relatedIdentifier":"10.1080/15476286.2014.996081","relatedIdentifierType":"DOI"},{"relationType":"IsPreviousVersionOf","relatedIdentifier":"10.6084/m9.figshare.1291145","relatedIdentifierType":"DOI"}],"relatedItems":[],"sizes":["3134002 Bytes"],"formats":[],"version":null,"rightsList":[{"rights":"Creative Commons Attribution 4.0 International","rightsUri":"https://creativecommons.org/licenses/by/4.0/legalcode","schemeUri":"https://spdx.org/licenses/","rightsIdentifier":"cc-by-4.0","rightsIdentifierScheme":"SPDX"}],"descriptions":[{"description":"TDP-43 is an RNA-binding protein involved in several steps of mRNA metabolism including transcription, splicing and stability. It is also involved in ALS and FTD, neurodegenerative diseases characterized by TDP-43 nuclear depletion. We previously identified TDP-43 as a binder of the downstream element (DSE) of the β\u003ci\u003e-Adducin\u003c/i\u003e (\u003ci\u003eAdd2\u003c/i\u003e) brain-specific polyadenylation site (A4 PAS), suggesting its involvement in pre-mRNA 3’ end processing. Here, by using chimeric minigenes, we showed that TDP-43 depletion in HeLa and HEK293 cells resulted in down-regulation of both the chimeric and endogenous \u003ci\u003eAdd2\u003c/i\u003e transcripts. Despite having confirmed TDP-43-DSE \u003ci\u003ein vitro\u003c/i\u003e interaction, we demonstrated that the \u003ci\u003ein vivo\u003c/i\u003e effect was not mediated by the TDP-43-DSE interaction. In fact, substitution of the Add2 DSE with viral E-SV40 and L-SV40 DSEs, which are not TDP-43 targets, still resulted in decreased \u003ci\u003eAdd2\u003c/i\u003e mRNA levels after TDP-43 down-regulation. In addition, we failed to show interaction between TDP-43 and key polyadenylation factors, such as CstF-64 and CPSF160 and excluded TDP-43 involvement in pre-mRNA cleavage and regulation of polyA tail length. These evidences allowed us to exclude the pre-hypothesized role of TDP43 in modulating 3’ end processing of Add2 pre-mRNA. Finally, we showed that TDP-43 regulates Add2 gene expression levels by increasing \u003ci\u003eAdd2\u003c/i\u003e mRNA stability. Considering that Add2 in brain participates in synapse assembly, synaptic plasticity and their stability, and its genetic inactivation in mice leads to LTP, LTD, learning and motor-coordination deficits, we hypothesize that a possible loss of Add2 function by TDP-43 depletion may contribute to ALS and FTD disease states.","descriptionType":"Abstract"}],"geoLocations":[],"fundingReferences":[],"xml":"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