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

Sébastien Küry, Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France. sebastien.kury@chu-nantes.fr.
Janelle E. Stanton, Bernal Institute, University of Limerick, Limerick, Ireland.
Geeske M. van Woerden, Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
Amélie Bosc-Rosati, Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse (UT), Toulouse, France.
Tzung-Chien Hsieh, Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
Lise Bray, Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
Marielle Oloudé, Nantes Université, CHU Nantes, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes, France.
Cory Rosenfelt, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
Marie Pier Scott-Boyer, Centre de recherche du CHU de Québec-Université Laval, Québec, QC, Canada.
Victoria Most, Institute for Drug Discovery, Medical Faculty, Leipzig University, Leipzig, Germany.
Tianyun Wang, Department of Medical Genetics, Center for Medical Genetics, Peking University Health Science Center, Beijing, China.
Jonas J. Papendorf, Universitätsmedizin Greifswald, Institut für Medizinische Biochemie und Molekularbiologie, Greifswald, Germany.
Charlotte de Konink, ENCORE Center of Expertise for Neurodevelopmental Disorders, Erasmus Medical Center, Rotterdam, The Netherlands.
Wallid Deb, Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France.
Virginie Vignard, Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
Maja Studencka-Turski, Universitätsmedizin Greifswald, Institut für Medizinische Biochemie und Molekularbiologie, Greifswald, Germany.
Thomas Besnard, Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France.
Anna M. Hajdukowicz, Universitätsmedizin Greifswald, Institut für Medizinische Biochemie und Molekularbiologie, Greifswald, Germany.
Franziska G. Thiel, Universitätsmedizin Greifswald, Institut für Medizinische Biochemie und Molekularbiologie, Greifswald, Germany.
Sophie Wolfgramm, Universitätsmedizin Greifswald, Institut für Medizinische Biochemie und Molekularbiologie, Greifswald, Germany.
Laëtitia Florenceau, Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
Silvestre Cuinat, Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France.
Sylvain Marsac, Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France.
Yann Verrès, Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
Audrey Dangoumau, Université de Tours, INSERM, Imaging Brain & Neuropsychiatry iBraiN U1253, Tours, France.
Léa Poirier, Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
Ingrid M. Wentzensen, GeneDx, LLC, Gaithersburg, MD, USA.
Annabelle Tuttle, GeneDx, LLC, Gaithersburg, MD, USA.
Cara Forster, Loyola University Chicago, Chicago, IL, USA.
Johanna Striesow, Leibniz Institute for Plasma Science and Technology (INP), Greifswald, Germany.
Richard Golnik, Department of Computer Science and Interdisciplinary Center for Bioinformatics, Bioinformatics Group, Universität Leipzig, Leipzig, Germany.
Damara Ortiz, UPMC Children's Hospital of Pittsburgh, One Children's Hospital Drive, Pittsburgh, PA, USA.

Document Type

Journal Article

Publication Date

11-26-2025

Journal

Nature communications

Volume

16

Issue

1

DOI

10.1038/s41467-025-65556-8

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.

Department

Pediatrics

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