Neddylation orchestrates the complex transcriptional and posttranscriptional program that drives Schwann cell myelination.
Por:
Ayuso-García P, Sánchez-Rueda A, Velasco-Avilés S, Tamayo-Caro M, Ferrer-Pinós A, Huarte-Sebastian C, Alvarez V, Riobello C, Jiménez-Vega S, Buendia I, Cañas-Martin J, Fernández-Susavila H, Aparicio-Rey A, Esquinas-Román EM, Ponte CR, Guhl R, Laville N, Pérez-Andrés E, Lavín JL, González-Lopez M, Cámara NM, Aransay AM, Lozano JJ, Sutherland JD, Barrio R, Martinez-Chantar ML, Azkargorta M, Elortza F, Soriano-Navarro M, Matute C, Sánchez-Gómez MV, Bayón-Cordero L, Pérez-Samartín A, Bravo SB, Kurz T, Lama-Díaz T, Blanco MG, Haddad S, Record CJ, van Hasselt PM, Reilly MM, Varela-Rey M and Woodhoo A
Publicada:
12 abr 2024
Resumen:
Myelination is essential for neuronal function and health. In peripheral nerves, >100 causative mutations have been identified that cause Charcot-Marie-Tooth disease, a disorder that can affect myelin sheaths. Among these, a number of mutations are related to essential targets of the posttranslational modification neddylation, although how these lead to myelin defects is unclear. Here, we demonstrate that inhibiting neddylation leads to a notable absence of peripheral myelin and axonal loss both in developing and regenerating mouse nerves. Our data indicate that neddylation exerts a global influence on the complex transcriptional and posttranscriptional program by simultaneously regulating the expression and function of multiple essential myelination signals, including the master transcription factor EGR2 and the negative regulators c-Jun and Sox2, and inducing global secondary changes in downstream pathways, including the mTOR and YAP/TAZ signaling pathways. This places neddylation as a critical regulator of myelination and delineates the potential pathogenic mechanisms involved in CMT mutations related to neddylation.
Filiaciones:
Ayuso-García P:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Sánchez-Rueda A:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Velasco-Avilés S:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Tamayo-Caro M:
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
Ferrer-Pinós A:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Huarte-Sebastian C:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Alvarez V:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Riobello C:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Jiménez-Vega S:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Buendia I:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Laboratory of Neurobiology, Achucarro Basque Center for Neuroscience, Science Park of UPV/EHU, Sede building, 48940 Leioa, Spain
Cañas-Martin J:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Fernández-Susavila H:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Aparicio-Rey A:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Esquinas-Román EM:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Ponte CR:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Guhl R:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Université Paris Cité Magistère Européen de Génétique, 85 Boulevard Saint-Germain, 75006 Paris, France
Laville N:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Université Paris Cité Magistère Européen de Génétique, 85 Boulevard Saint-Germain, 75006 Paris, France
Pérez-Andrés E:
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
Lavín JL:
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
NEIKER-Basque Institute for Agricultural Research and Development, Applied Mathematics Department, Bioinformatics Unit, Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain
González-Lopez M:
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
Cámara NM:
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
Aransay AM:
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
Lozano JJ:
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
Sutherland JD:
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
Barrio R:
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
Martinez-Chantar ML:
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
Azkargorta M:
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
Elortza F:
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
:
Electron Microscopy Core Facility, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain
Matute C:
Laboratory of Neurobiology, Achucarro Basque Center for Neuroscience, Science Park of UPV/EHU, Sede building, 48940 Leioa, Spain
Department of Neurosciences, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
Sánchez-Gómez MV:
Laboratory of Neurobiology, Achucarro Basque Center for Neuroscience, Science Park of UPV/EHU, Sede building, 48940 Leioa, Spain
Department of Neurosciences, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
Bayón-Cordero L:
Laboratory of Neurobiology, Achucarro Basque Center for Neuroscience, Science Park of UPV/EHU, Sede building, 48940 Leioa, Spain
Department of Neurosciences, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
Pérez-Samartín A:
Laboratory of Neurobiology, Achucarro Basque Center for Neuroscience, Science Park of UPV/EHU, Sede building, 48940 Leioa, Spain
Department of Neurosciences, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain
Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
Bravo SB:
Proteomic Unit, Health Research Institute of Santiago de Compostela (IDIS), 15705 Santiago de Compostela, A Coruña, Spain
Kurz T:
Evotec SE, Innovation Dr, Milton, Abingdon OX14 4RT, UK and School of Molecular Biosciences, University of Glasgow, Glasgow G12 8QQ, UK
Lama-Díaz T:
DNA Repair and Genome Integrity Laboratory, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15706 Santiago de Compostela, A Coruña, Spain
Blanco MG:
DNA Repair and Genome Integrity Laboratory, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15706 Santiago de Compostela, A Coruña, Spain
Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Plaza do Obradoiro s/n, Santiago de Compostela, Spain
Haddad S:
Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
Record CJ:
Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
van Hasselt PM:
Department of Metabolic Diseases, Division Pediatrics, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University, 3584 EA, Utrecht, Netherlands
Reilly MM:
Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
Varela-Rey M:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Plaza do Obradoiro s/n, Santiago de Compostela, Spain
Woodhoo A:
Gene Regulatory Control in Disease Laboratory, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), University of Santiago de Compostela, 15706 Santiago de Compostela, A Coruña, Spain
Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain
IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Bizkaia, Spain
Department of Functional Biology, University of Santiago de Compostela, Plaza do Obradoiro s/n, Santiago de Compostela, Spain
Oportunius Research Professor at CIMUS/USC, Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, A Coruña, Spain
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