2. Academic Validation
  3. Neddylation orchestrates the complex transcriptional and posttranscriptional program that drives Schwann cell myelination

Neddylation orchestrates the complex transcriptional and posttranscriptional program that drives Schwann cell myelination

  • Sci Adv. 2024 Apr 12;10(15):eadm7600. doi: 10.1126/sciadv.adm7600.
Paula Ayuso-García 1,  Alejandro Sánchez-Rueda 1,  Sergio Velasco-Avilés 1,  Miguel Tamayo-Caro 2,  Aroa Ferrer-Pinós 1,  Cecilia Huarte-Sebastian 1,  Vanesa Alvarez 1,  Cristina Riobello 1,  Selene Jiménez-Vega 1,  Izaskun Buendia 1 3,  Jorge Cañas-Martin 1,  Héctor Fernández-Susavila 1,  Adrián Aparicio-Rey 1,  Eva M Esquinas-Román 1,  Carlos Rodríguez Ponte 1,  Romane Guhl 1 4,  Nicolas Laville 1 4,  Encarni Pérez-Andrés 2,  José L Lavín 2 5,  Monika González-Lopez 2,  Nuria Macías Cámara 2,  Ana M Aransay 2 6,  Juan José Lozano 6,  James D Sutherland 2,  Rosa Barrio 2,  María Luz Martinez-Chantar 2 6,  Mikel Azkargorta 2,  Félix Elortza 2,  Mario Soriano-Navarro 7,  Carlos Matute 3 8 9,  María Victoria Sánchez-Gómez 3 8 9,  Laura Bayón-Cordero 3 8 9,  Alberto Pérez-Samartín 3 8 9,  Susana B Bravo 10,  Thimo Kurz 11,  Tomas Lama-Díaz 12,  Miguel G Blanco 12 13,  Saif Haddad 14,  Christopher J Record 14,  Peter M van Hasselt 15,  Mary M Reilly 14,  Marta Varela-Rey 1 13,  Ashwin Woodhoo 1 2 16 17 18
Affiliations

Affiliations

  • 1 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.
  • 2 Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, 48160 Derio, Spain.
  • 3 Laboratory of Neurobiology, Achucarro Basque Center for Neuroscience, Science Park of UPV/EHU, Sede building, 48940 Leioa, Spain.
  • 4 Université Paris Cité Magistère Européen de Génétique, 85 Boulevard Saint-Germain, 75006 Paris, France.
  • 5 NEIKER-Basque Institute for Agricultural Research and Development, Applied Mathematics Department, Bioinformatics Unit, Basque Research and Technology Alliance (BRTA), 48160 Derio, Bizkaia, Spain.
  • 6 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
  • 7 Electron Microscopy Core Facility, Centro de Investigación Príncipe Felipe (CIPF), 46012 Valencia, Spain.
  • 8 Department of Neurosciences, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.
  • 9 Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain.
  • 10 Proteomic Unit, Health Research Institute of Santiago de Compostela (IDIS), 15705 Santiago de Compostela, A Coruña, Spain.
  • 11 Evotec SE, Innovation Dr, Milton, Abingdon OX14 4RT, UK and School of Molecular Biosciences, University of Glasgow, Glasgow G12 8QQ, UK.
  • 12 DNA Repair and Genome Integrity Laboratory, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, 15706 Santiago de Compostela, A Coruña, Spain.
  • 13 Department of Biochemistry and Molecular Biology, University of Santiago de Compostela, Plaza do Obradoiro s/n, Santiago de Compostela, Spain.
  • 14 Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
  • 15 Department of Metabolic Diseases, Division Pediatrics, Wilhelmina Children's Hospital University Medical Center Utrecht, Utrecht University, 3584 EA, Utrecht, Netherlands.
  • 16 IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Bizkaia, Spain.
  • 17 Department of Functional Biology, University of Santiago de Compostela, Plaza do Obradoiro s/n, Santiago de Compostela, Spain.
  • 18 Oportunius Research Professor at CIMUS/USC, Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, A Coruña, Spain.
PMID: 38608019 DOI: 10.1126/sciadv.adm7600
Abstract

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.

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