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

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.

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Journal
Nature Communications
Published
2025-11-26
DOI
https://doi.org/10.1038/s41467-025-65556-8
Citations
2
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
1.61

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article

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

Marta Codina‐Solà, Athina Ververi, Michelle L. Thompson, Zdeněk Sedláček et al.
2 citations
Nature Communications
Ubiquitin and proteasome pathways
1.61
article

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

Marta Codina‐Solà, Athina Ververi, Michelle L. Thompson, Zdeněk Sedláček, Siddharth Srivastava, Cory Rosenfelt, Sureni V. Mullegama, Frédéric Ebstein, Trevor L. Hoffman, Elsa Wiame, Kira A. Dies, Janelle E. Stanton, Rachel B. Smith, Kyriakos Garganis, Karen Kovak, Sacha Weber, Rebecca D. Ganetzky, Andrew T. Timberlake, Lisa Bryson, Catharina M.L. Volker‐Touw, Arti Pandya, Marie‐Pierre Bousquet, Frédéric Laumonnier, Marie‐Pier Scott‐Boyer, David R. Adams, Jonathan Lévy, Evan E. Eichler, Hind Al Saif, Davit Babikyan, Daniela D’Agostino, Franziska G. Thiel, Cara Forster, Charlotte de Konink, Alali Abdulrazak, Ingrid M. Wentzensen, M.J. Hajianpour, Rebekah Jobling, Florence Roux‐Dalvai, Jens Meiler, Anne Chun‐Hui Tsai, Susanne B. Kamphausen, Ivan P. Ivanovski, John Pappas, Lorraine Potocki, Christophe Philippe, Virginie Vignard, Αlexandros Lampropoulos, Thomas Besnard, Sébastien Küry, Damara Ortiz, Ataf Sabir, Katharina Steindl, Noelle Andrea V. Fabie, Andrew Dauber, Anna M. Cueto‐González, Anita M. Rauch, Koen L.I. van Gassen, Marlène Rio, Peter Krawitz, Amber Begtrup, Silvestre Cuinat, David Gómez‐Andrés, Clémentine Ripoll, Laëtitia Florenceau, Kristian Wende, Jérémie Poschmann, May Christine V. Malicdan, Gregory Costain, Jill Anne Rosenfeld, Efterpi Pavlidou, David B. Beck, Erin Torti, Richard Golnik, Sarah Jurgensmeyer, Mathieu Lessard, Tamar Harel, Raphael Bernier, Rachel Rabin, Elke Hammer, Janice Baker, Alban Ziegler, Antonio Vitobello, Lise Bray, Geeske M. van Woerden, Ype Elgersma, Julien Marcoux, Chumei Li, Kayla King, Renske Oegema, Kimberly S. McDonald, Arthur Sorlin, Isabelle De Bie, Eric Olinger, Tychele N. Turner, Laura Jenkins, Tzung‐Chien Hsieh, Mirjam S. de Pagter, Molly C. Schroeder, Viktoria Bothe, Peter W. Hildebrand, Arnaud Droit, Ori Toker, Jonas Johannes Papendorf, Victoria Most, Miroslava Hančárová, Elaine Cleary, Dominique Bonneau, Yann Verrès, Lynne A. Wolfe, Eduardo F. Tizzano, Sylvain Marsac, Rami Abou Jamra, Mark Hamilton, D’Arcy Prendergast, David Geneviève, Yves Sznajer, Meret Wegler, Wallid Deb, Andreas Martin Grabrucker, François V. Bolduc, Annabelle Tuttle, Maja Studencka‐Turski, Catherine Gooch, Anne McRae, Uwe Völker, Johanna Striesow, Stéphane Bezieau, Audrey Dangoumau, Larissa Milena Busch, Kirsty McWalter, Colleen Muraresku, Emily Boothe, Stéphanie Bigou, Anna Marta Hajdukowicz, Amélie Bosc-Rosati, Kristin G. Monaghan, Dmitriy Niyazov, Tianyun Wang, Clara Houdayer, Bertrand Isidor, Berkley Nestler, Derek Lim, Benjamin Cogné, Léa Poirier, Carrie Costin, Sophie Möller, Elke Krüger, Lindsay C. Swanson, Marielle Oloudé
article en
2 citations

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.

Nature CommunicationsVol. 16(1)
Université de Tours (FR), King University (US), Northwestern University (US), University of North Carolina at Chapel Hill (US), West Virginia University (US), George Washington University Hospital (US), Hôpital Necker-Enfants Malades (FR), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), Cliniques Universitaires Saint-Luc (BE), Children's Hospital of Philadelphia (US), Children's National (US), Howard Hughes Medical Institute (US), University of Bonn (DE), University of Louisville (US), University of Alberta (CA), Inserm (FR), University of Illinois Urbana-Champaign (US), Oregon Health & Science University (US), Duke University (US), Université de Bourgogne (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Baylor College of Medicine (US), Virginia Commonwealth University (US), University of Toronto (CA), Loyola University Chicago (US), George Washington University (US), Utrecht University (NL), Hebrew University of Jerusalem (IL), Université de Montpellier (FR), Vanderbilt University (US), University of Washington (US), Peking University (CN), University of Zurich (CH), Washington University in St. Louis (US), Charles University (CZ), University of Limerick (IE), National Health and Family Planning Commission (CN), Universitätsmedizin Greifswald (DE), University Hospital Bonn (DE), Hadassah Medical Center (IL), Western General Hospital (GB), McMaster University Medical Centre (CA), Hospital for Sick Children (CA), McGill University Health Centre (CA), Erasmus MC (NL), Shaare Zedek Medical Center (IL), Jackson Memorial Hospital (US), West Virginia University Hospitals (US), University of Mississippi Medical Center (US), University Medical Center Utrecht (NL), Centre Hospitalier Universitaire de Nantes (FR), Universität Greifswald (DE), Humboldt-Universität zu Berlin (DE), University of Illinois Chicago (US), Sorbonne Université (FR), Telstra (Australia) (AU), Hôpital Armand-Trousseau (FR), NYU Langone Health (US), Leibniz Institute for Plasma Science and Technology (DE), National Human Genome Research Institute (US), Centre Hospitalier Universitaire de Tours (FR), Assistance Publique – Hôpitaux de Paris (FR), Akron Children's Hospital (US), Institut de Pharmacologie et de Biologie Structurale (FR), St. Luke's Hospital (GR), Vall d'Hebron Institut de Recerca (ES), Papageorgiou General Hospital (GR), Center for Human Genetics (US), Ministry of Education (ME), Centre Hospitalier Universitaire d'Angers (FR), Behavioral Tech Research, Inc. (US), CHU Dijon Bourgogne (FR), Université Bourgogne Franche-Comté (FR), McGill Genome Centre (CA), Lurie Children's Hospital (US), UK Dementia Research Institute (GB), Hôpital Robert-Debré (FR), Vall d'Hebron Hospital Universitari (ES), Centre d'Investigation Clinique de Nantes (FR), University Children's Hospital Zurich (CH), Children's Hospital of Pittsburgh (US), Women and Children’s Health Research Institute (CA), Children's Minnesota (US), University Hospital Magdeburg (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), SickKids Foundation (CA), University Hospital of Ioannina (GR), Institut du Thorax (FR), Kaiser Permanente Anaheim Medical Center (US), Cancer Genetics (United States) (US), Hôpital Arnaud de Villeneuve (FR), Texas Children's Hospital (US), Center of Medical Genetics and Primary Health Care (AM), Institut du Cerveau (FR), Birmingham Women’s and Children’s NHS Foundation Trust (GB), Fondation pour la Recherche Médicale (FR), Génétique Médicale & Génomique Fonctionelle (FR), Queen Elizabeth University Hospital (GB), Baylor Genetics (US), French Clinical Research Infrastructure Network (FR), Université Laval (CA), Center for Research in Transplantation and Translational Immunology, Université d'Angers (FR), New York University (US), Yerevan State Medical University (AM), Albany Medical Center Hospital (US), University of Pennsylvania (US), University of Birmingham (GB), Leipzig University (DE), Nantes Université (FR), University of Edinburgh (GB)
European Commission, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, National Natural Science Foundation of China, Bundesministerium für Bildung und Forschung, National Institutes of Health, Fundamental Research Funds for the Central Universities, National Institute of Neurological Disorders and Stroke
Openalex Percentile: Top 14%
Ubiquitin and proteasome pathways
1.61
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