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dc.contributor.authorRossi, Chiara
dc.contributor.authorFernàndez, Anna
dc.contributor.authorTorres Cabestany, Pascual
dc.contributor.authorRamírez Núñez, Omar
dc.contributor.authorGranado-Serrano, Ana Belén
dc.contributor.authorFontdevila, Laia
dc.contributor.authorPovedano, Mònica
dc.contributor.authorPamplona Gras, Reinald
dc.contributor.authorFerrer, Isidre
dc.contributor.authorPortero Otín, Manuel
dc.description.abstractPrevious evidence links the formation of extranuclear inclusions of transcription factors, such as ERK, Jun, TDP-43, and REST, with oxidative, endoplasmic-reticulum, proteasomal, and osmotic stress. To further characterize its extranuclear location, we performed a high-content screening based on confocal microscopy and automatized image analyses of an epithelial cell culture treated with hydrogen peroxide, thapsigargin, epoxomicin, or sorbitol at different concentrations and times to recreate the stresses mentioned above. We also performed a subcellular fractionation of the brain from transgenic mice overexpressing the Q331K-mutated TARDBP, and we analyzed the REST-regulated mRNAs. The results show that these nuclear proteins exhibit a mitochondrial location, together with significant nuclear/extranuclear ratio changes, in a protein and stress-specific manner. The presence of these proteins in enriched mitochondrial fractions in vivo confirmed the results of the image analyses. TDP-43 aggregation was associated with alterations in the mRNA levels of the REST target genes involved in calcium homeostasis, apoptosis, and metabolism. In conclusion, cell stress increased the mitochondrial translocation of nuclear proteins, increasing the chance of proteostasis alterations. Furthermore, TDP-43 aggregation impacts REST target genes, disclosing an exciting interaction between these two transcription factors in neurodegenerative processes.ca_ES
dc.description.sponsorshipThis research was funded by the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (PI 17–00134, PI20-0155) to M.P-O, from the Spanish Ministry ofScience, Innovation, and Universities (RTI2018-099200-B-I00), and the Generalitat of Catalonia (Agency for Management of University and Research Grants (2017SGR696) and Department ofHealth (SLT002/16/00250) to RP. PT was a predoctoral fellow from the Ministerio de Educacion(FPU16/01446). CR and LF held predoctoral fellowships “Ajuts 2020 & 2021 de Promocióde laRecerca en Salut -8ª edició” from IRBLleida/Diputacióde Lleida. Support was also received inthe form of a Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica (FUNDELA] Grant, RedELA-Plataforma Investigación, and the Fundació Miquel Valls (Jack Van den Hoek donation]. This study was co-financed by FEDER funds from the European Union (“A way to build Europe”). IRBLleida is funded by a Centres de Recerca de Catalunya (CERCA)Programme/Generalitat of Catalonia.ca_ES
dc.relation.isformatofReproducció del document publicat a:
dc.relation.ispartofInternational Journal Of Molecular Sciences, 2021, vol. 22, núm. 16ca_ES
dc.rightscc-by (c) Authors, 2021ca_ES
dc.subjectCell stressca_ES
dc.subjectSubcellular fractionationca_ES
dc.subjectTranscription factorsca_ES
dc.subjectTransgenic miceca_ES
dc.titleCell Stress Induces Mislocalization of Transcription Factors with Mitochondrial Enrichmentca_ES

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