Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies

Sébastien Küry (), Janelle E. Stanton, Geeske M. van Woerden, Amélie Bosc-Rosati, Tzung-Chien Hsieh, Lise Bray, Marielle Oloudé, Cory Rosenfelt, Marie Pier Scott-Boyer, Victoria Most, Tianyun Wang, Jonas J. Papendorf, Charlotte de Konink, Wallid Deb, Virginie Vignard, Maja Studencka-Turski, Thomas Besnard, Anna M. Hajdukowicz, Franziska G. Thiel, Sophie Wolfgramm, Laëtitia Florenceau, Silvestre Cuinat, Sylvain Marsac, Yann Verrès, Audrey Dangoumau, Léa Poirier, Ingrid M. Wentzensen, Annabelle Tuttle, Cara Forster, Johanna Striesow, Richard Golnik, Damara Ortiz, Laura Jenkins, Jill A. Rosenfeld, Alban Ziegler, Clara Houdayer, Dominique Bonneau, Erin Torti, Amber Begtrup, Kristin G. Monaghan, Sureni V. Mullegama, Catharina M. L. Nienke Volker-Touw, Koen L. I. van Gassen, Renske Oegema, Mirjam S. de Pagter, Katharina Steindl, Anita Rauch, Ivan Ivanovski, Kimberly McDonald, Emily Boothe, Andrew Dauber, Janice Baker, Noelle Andrea V. Fabie, Raphael A. Bernier, Tychele N. Turner, Siddharth Srivastava, Kira A. Dies, Lindsay C. Swanson, Carrie Costin, Alali Abdulrazak, Rebekah K. Jobling, John Pappas, Rachel Rabin, Dmitriy Niyazov, Anne Chun-Hui Tsai, Karen Kovak, David B. Beck, May Christine V. Malicdan, David R. Adams, Lynne Wolfe, Rebecca D. Ganetzky, Colleen C. Muraresku, Davit Babikyan, Zdeněk Sedláček, Miroslava Hančárová, Andrew T. Timberlake, Hind Al Saif, Berkley Nestler, Kayla King, Hajianpour Mj, Gregory Costain, D’Arcy Prendergast, Chumei Li, David Geneviève, Antonio Vitobello, Arthur Sorlin, Christophe Philippe, Tamar Harel, Ori Toker, Ataf Sabir, Derek Lim, Mark J. Hamilton, Lisa J. Bryson, Elaine Cleary, Sacha Weber, Trevor L. Hoffman, Anna M. Cueto-González, Eduardo F. Tizzano, David Gómez-Andrés, Marta Codina-Solà, Athina Ververi, Efterpi Pavlidou, Alexandros Lambropoulos, Kyriakos Garganis, Marlène Rio, Jonathan Levy, Sarah J. Langas, Anne M. McRae, Mathieu K. Lessard, Maria Daniela D’Agostino, Isabelle De Bie, Meret Wegler, Rami Abou Jamra, Susanne B. Kamphausen, Viktoria Bothe, Lorraine Potocki, Eric Olinger, Yves Sznajer, Elsa Wiame, Michelle L. Thompson, Molly C. Schroeder, Catherine Gooch, Raphael A. Smith, Arti Pandya, Larissa M. Busch, Uwe Völker, Elke Hammer, Kristian Wende, Benjamin Cogné, Bertrand Isidor, Jens Meiler, Clémentine Ripoll, Stéphanie Bigou, Frédéric Laumonnier, Peter W. Hildebrand, Evan E. Eichler, Kirsty McWalter, Peter M. Krawitz, Florence Roux-Dalvai, Ype Elgersma, Julien Marcoux, Marie-Pierre Bousquet, Arnaud Droit, Jeremie Poschmann, Andreas M. Grabrucker, Francois V. Bolduc, Stéphane Bézieau (), Frédéric Ebstein () and Elke Krüger ()
Additional contact information
Sébastien Küry: Nantes Université, CHU Nantes, Service de Génétique Médicale
Janelle E. Stanton: University of Limerick, Bernal Institute
Geeske M. van Woerden: Erasmus Medical Center, Department of Clinical Genetics
Amélie Bosc-Rosati: Université de Toulouse (UT), Institut de Pharmacologie et de Biologie Structurale (IPBS)
Tzung-Chien Hsieh: Rheinische Friedrich-Wilhelms-Universität Bonn, Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Lise Bray: Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax
Marielle Oloudé: Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology
Cory Rosenfelt: University of Alberta, Department of Pediatrics
Marie Pier Scott-Boyer: Centre de recherche du CHU de Québec-Université Laval
Victoria Most: Leipzig University, Institute for Drug Discovery, Medical Faculty
Tianyun Wang: Peking University Health Science Center, Department of Medical Genetics, Center for Medical Genetics
Jonas J. Papendorf: Institut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald
Charlotte de Konink: Erasmus Medical Center, ENCORE Center of Expertise for Neurodevelopmental Disorders
Wallid Deb: Nantes Université, CHU Nantes, Service de Génétique Médicale
Virginie Vignard: Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax
Maja Studencka-Turski: Institut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald
Thomas Besnard: Nantes Université, CHU Nantes, Service de Génétique Médicale
Anna M. Hajdukowicz: Institut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald
Franziska G. Thiel: Institut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald
Sophie Wolfgramm: Institut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald
Laëtitia Florenceau: Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax
Silvestre Cuinat: Nantes Université, CHU Nantes, Service de Génétique Médicale
Sylvain Marsac: Nantes Université, CHU Nantes, Service de Génétique Médicale
Yann Verrès: Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax
Audrey Dangoumau: Université de Tours, INSERM, Imaging Brain & Neuropsychiatry iBraiN U1253
Léa Poirier: Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax
Ingrid M. Wentzensen: GeneDx, LLC
Annabelle Tuttle: GeneDx, LLC
Cara Forster: Loyola University Chicago
Johanna Striesow: Leibniz Institute for Plasma Science and Technology (INP)
Richard Golnik: Universität Leipzig, Department of Computer Science and Interdisciplinary Center for Bioinformatics, Bioinformatics Group
Damara Ortiz: UPMC Children’s Hospital of Pittsburgh, One Children’s Hospital Drive
Laura Jenkins: UPMC Children’s Hospital of Pittsburgh, One Children’s Hospital Drive
Jill A. Rosenfeld: Baylor College of Medicine, Department of Molecular and Human Genetics
Alban Ziegler: University Hospital of Toulouse, Department of Medical Genetics
Clara Houdayer: Service de Génétique médicale, CHU Angers
Dominique Bonneau: Service de Génétique médicale, CHU Angers
Erin Torti: GeneDx, LLC
Amber Begtrup: GeneDx, LLC
Kristin G. Monaghan: GeneDx, LLC
Sureni V. Mullegama: GeneDx, LLC
Catharina M. L. Nienke Volker-Touw: Utrecht University, Department of Genetics, University Medical Centre Utrecht
Koen L. I. van Gassen: Utrecht University, Department of Genetics, University Medical Centre Utrecht
Renske Oegema: Utrecht University, Department of Genetics, University Medical Centre Utrecht
Mirjam S. de Pagter: Utrecht University, Department of Genetics, University Medical Centre Utrecht
Katharina Steindl: University of Zürich, Institute of Medical Genetics
Anita Rauch: University of Zürich, Institute of Medical Genetics
Ivan Ivanovski: University of Zürich, Institute of Medical Genetics
Kimberly McDonald: University of Louisville School of Medicine, Norton Children’s Medical Group
Emily Boothe: University of Mississippi Medical Center
Andrew Dauber: The George Washington University School of Medicine and Health Sciences, Division of Endocrinology, Children’s National Hospital and Department of Pediatrics
Janice Baker: Children’s Minnesota, Department of Medical Genetics and Genomics
Noelle Andrea V. Fabie: Children’s Minnesota, Department of Medical Genetics and Genomics
Raphael A. Bernier: University of Washington, Department of Psychiatry & Behavioral Sciences, Center on Human Development and Disability
Tychele N. Turner: Washington University School of Medicine, Department of Genetics
Siddharth Srivastava: Boston Children’s Hospital, Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology
Kira A. Dies: Boston Children’s Hospital, Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology
Lindsay C. Swanson: Boston Children’s Hospital, Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology
Carrie Costin: Akron Children’s Hospital, One Perkins Square, Department of Genetics
Alali Abdulrazak: West Virginia University School of Medicine, One Medical Center Drive, Division of Genetics, Department of Pediatrics
Rebekah K. Jobling: The Hospital for Sick Children, Division of Clinical and Metabolic Genetics
John Pappas: NYU Grossman School of Medicine, Clinical Genetic Services, Department of Pediatrics
Rachel Rabin: NYU Grossman School of Medicine, Clinical Genetic Services, Department of Pediatrics
Dmitriy Niyazov: Duke University School of Medicine, Division of Medical Genetics, Department of Pediatrics
Anne Chun-Hui Tsai: University of Illinois, Department of Pediatrics, College of Medicine
Karen Kovak: Oregon Health and Sciences University, OHSU, Department of Molecular and Medical Genetics
David B. Beck: New York University Grossman School of Medicine, Division of Rheumatology, Department of Medicine
May Christine V. Malicdan: National Human Genome Research Institute, NIH, Medical Genetics Branch
David R. Adams: National Human Genome Research Institute, NIH, National Institutes of Health Undiagnosed Diseases Program
Lynne Wolfe: National Human Genome Research Institute, NIH, National Institutes of Health Undiagnosed Diseases Program
Rebecca D. Ganetzky: Children’s Hospital of Philadelphia, Mitochondrial Medicine Program, Division of Human Genetics
Colleen C. Muraresku: Children’s Hospital of Philadelphia, Mitochondrial Medicine Program, Division of Human Genetics
Davit Babikyan: Yerevan State Medical University after Mkhitar Heratsi, Department of Medical Genetics
Zdeněk Sedláček: Charles University 2nd Faculty of Medicine and University Hospital Motol, Department of Biology and Medical Genetics
Miroslava Hančárová: Charles University 2nd Faculty of Medicine and University Hospital Motol, Department of Biology and Medical Genetics
Andrew T. Timberlake: NYU Langone Medical Center, Wyss Department of Plastic Surgery
Hind Al Saif: Virginia Commonwealth University School of Medicine, Department of Human and Molecular Genetics, Division of Clinical Genetics
Berkley Nestler: Virginia Commonwealth University School of Medicine, Department of Human and Molecular Genetics, Division of Clinical Genetics
Kayla King: Virginia Commonwealth University School of Medicine, Department of Human and Molecular Genetics, Division of Clinical Genetics
Hajianpour Mj: Albany Medical College, Division of Medical Genetics and Genomics, Department of Pediatrics
Gregory Costain: The Hospital for Sick Children, Division of Clinical and Metabolic Genetics
D’Arcy Prendergast: The Hospital for Sick Children, Division of Clinical and Metabolic Genetics
Chumei Li: McMaster University Medical Center
David Geneviève: Hôpital Arnaud de Villeneuve, Université Montpellier, Inserm U 1183, Centre de référence maladies rares anomalies du développement, Service de génétique médicale
Antonio Vitobello: Université de Bourgogne Franche Comté, UMR 1231 GAD, Inserm
Arthur Sorlin: Université de Bourgogne Franche Comté, UMR 1231 GAD, Inserm
Christophe Philippe: Université de Bourgogne Franche Comté, UMR 1231 GAD, Inserm
Tamar Harel: Hadassah Medical Organization, Department of Genetics
Ori Toker: Hebrew University of Jerusalem, Department of Pediatrics, Allergy and Clinical Immunology Unit, Shaare Zedek Medical Center, Faculty of Medicine
Ataf Sabir: Birmingham Women’s and Children’s NHS Foundation Trust, Clinical Genetics Department
Derek Lim: Birmingham Women’s and Children’s NHS Foundation Trust, Clinical Genetics Department
Mark J. Hamilton: Queen Elizabeth University Hospital, West of Scotland Clinical Genetics Service
Lisa J. Bryson: Queen Elizabeth University Hospital, West of Scotland Clinical Genetics Service
Elaine Cleary: Western General Hospital, South East Scotland Genetics Service
Sacha Weber: Sorbonne Université, Service de Génétique Médicale, Hôpital Armand-Trousseau, APHP
Trevor L. Hoffman: Southern California Kaiser Permanente Medical Group, Department of Genetics
Anna M. Cueto-González: Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Department of Clinical and Molecular Genetics
Eduardo F. Tizzano: Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Department of Clinical and Molecular Genetics
David Gómez-Andrés: Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Pediatric Neurology, Vall d’Hebron Institut de Recerca (VHIR)
Marta Codina-Solà: Vall d’Hebron Hospital Universitari, Vall d’Hebron Barcelona Hospital Campus, Department of Clinical and Molecular Genetics
Athina Ververi: ‘Papageorgiou’ General Hospital, Department of Genetics for Rare Diseases
Efterpi Pavlidou: University Hospital of Ioannina, Department of Speech and Language Therapy
Alexandros Lambropoulos: Aristotle University of Thessaloniki, ‘Papageorgiou’ General Hospital, Genetic Unit, 1st Department of Obstetrics and Gynecology, School of Medicine
Kyriakos Garganis: St Luke’s Hospital, Epilepsy Unit
Marlène Rio: Hôpital Necker-Enfants Malades, AP-HP, Service de Médecine Génomique des Maladies Rares
Jonathan Levy: APHP-Robert Debré University Hospital, Department of Genetics
Sarah J. Langas: Ann & Robert H. Lurie Children’s Hospital of Chicago, Division of Genetics, Genomics and Metabolism
Anne M. McRae: Ann & Robert H. Lurie Children’s Hospital of Chicago, Division of Genetics, Genomics and Metabolism
Mathieu K. Lessard: McGill University, Division of Medical Genetics, Department of Specialised Medicine, McGill University Health Centre, Department of Human Genetics
Maria Daniela D’Agostino: McGill University, Division of Medical Genetics, Department of Specialised Medicine, McGill University Health Centre, Department of Human Genetics
Isabelle De Bie: McGill University, Division of Medical Genetics, Department of Specialised Medicine, McGill University Health Centre, Department of Human Genetics
Meret Wegler: University of Leipzig Medical Center, Institute of Human Genetics
Rami Abou Jamra: University of Leipzig Medical Center, Institute of Human Genetics
Susanne B. Kamphausen: University Hospital Magdeburg, Institute of Human Genetics, University Hospital Magdeburg
Viktoria Bothe: University of Leipzig Medical Center, Institute of Human Genetics
Lorraine Potocki: Baylor College of Medicine, Department of Molecular and Human Genetics
Eric Olinger: Cliniques Universitaires Saint-Luc, UCLouvain, Center for Human Genetics
Yves Sznajer: Cliniques Universitaires Saint-Luc, UCLouvain, Center for Human Genetics
Elsa Wiame: Cliniques Universitaires Saint-Luc, UCLouvain, Center for Human Genetics
Michelle L. Thompson: Washington University School of Medicine in Saint Louis, Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine
Molly C. Schroeder: Washington University School of Medicine in Saint Louis, Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine
Catherine Gooch: Washington University in St Louis, Department of Pediatrics, Division of Genetics and Genomic Medicine
Raphael A. Smith: University of North Carolina Health, Department of Pediatrics, Division of Genetics and Metabolism
Arti Pandya: University of North Carolina Health, Department of Pediatrics, Division of Genetics and Metabolism
Larissa M. Busch: Abteilung für Funktionelle Genomforschung, Universitätsmedizin Greifswald, Interfakultäres Institut für Genetik und Funktionelle Genomforschung
Uwe Völker: Abteilung für Funktionelle Genomforschung, Universitätsmedizin Greifswald, Interfakultäres Institut für Genetik und Funktionelle Genomforschung
Elke Hammer: Abteilung für Funktionelle Genomforschung, Universitätsmedizin Greifswald, Interfakultäres Institut für Genetik und Funktionelle Genomforschung
Kristian Wende: Leibniz Institute for Plasma Science and Technology (INP)
Benjamin Cogné: Nantes Université, CHU Nantes, Service de Génétique Médicale
Bertrand Isidor: Nantes Université, CHU Nantes, Service de Génétique Médicale
Jens Meiler: Leipzig University, Institute for Drug Discovery, Medical Faculty
Clémentine Ripoll: Hôpital de la Pitié Salpêtrière, ICV-iPS core facility, Sorbonne Université, Institut du Cerveau—Paris Brain Institute—ICM, Inserm, CNRS, APHP
Stéphanie Bigou: Hôpital de la Pitié Salpêtrière, ICV-iPS core facility, Sorbonne Université, Institut du Cerveau—Paris Brain Institute—ICM, Inserm, CNRS, APHP
Frédéric Laumonnier: Université de Tours, INSERM, Imaging Brain & Neuropsychiatry iBraiN U1253
Peter W. Hildebrand: Universität Leipzig, Medizinische Fakultät, Institut für Medizinische Physik und Biophysik
Evan E. Eichler: University of Washington School of Medicine, Department of Genome Sciences
Kirsty McWalter: GeneDx, LLC
Peter M. Krawitz: Rheinische Friedrich-Wilhelms-Universität Bonn, Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Florence Roux-Dalvai: Centre de recherche du CHU de Québec-Université Laval
Ype Elgersma: Erasmus Medical Center, Department of Clinical Genetics
Julien Marcoux: Université de Toulouse (UT), Institut de Pharmacologie et de Biologie Structurale (IPBS)
Marie-Pierre Bousquet: Université de Toulouse (UT), Institut de Pharmacologie et de Biologie Structurale (IPBS)
Arnaud Droit: Centre de recherche du CHU de Québec-Université Laval
Jeremie Poschmann: Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology
Andreas M. Grabrucker: University of Limerick, Bernal Institute
Francois V. Bolduc: University of Alberta, Department of Pediatrics
Stéphane Bézieau: Nantes Université, CHU Nantes, Service de Génétique Médicale
Frédéric Ebstein: Nantes Université, CHU Nantes, CNRS, INSERM, l’institut du thorax
Elke Krüger: Institut für Medizinische Biochemie und Molekularbiologie, Universitätsmedizin Greifswald

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Neurodevelopmental proteasomopathies are a group of disorders caused by variants in proteasome subunit genes, that disrupt protein homeostasis and brain development through poorly characterized mechanisms. Here, we report 26 distinct variants in PSMC5, encoding the AAA⁺ ATPase subunit PSMC5/RPT6, in individuals with syndromic neurodevelopmental conditions. Combining genetic, multi-omics and biochemical approaches across cellular models and Drosophila, we unveil the essential role of proteasomes in sustaining key cellular processes. Loss of PSMC5/RPT6 function impairs proteasome activity, leading to protein aggregation, disruption of mitochondrial homeostasis, and dysregulation of lipid metabolism and immune signaling. It also compromises synaptic balance, neuritogenesis, and neural progenitor cell stemness, causing deficits in higher-order functions, including learning and locomotion. Pharmacological targeting of integrated stress response kinases reveals a mechanistic link between proteotoxic stress and spontaneous type I interferon activation. These findings expand our understanding of proteasome-dependent quality control in neurodevelopment and suggest potential therapeutic strategies for neurodevelopmental proteasomopathies.

Date: 2025
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DOI: 10.1038/s41467-025-65556-8

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