| Title: |
Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies |
| Authors: |
Küry, Sébastien; Stanton, Janelle; van Woerden, Geeske; Bosc-Rosati, Amélie; Hsieh, Tzung-Chien; Bray, Lise; Oloudé, Marielle; Rosenfelt, Cory; Scott-Boyer, Marie Pier; Most, Victoria; Wang, Tianyun; Papendorf, Jonas; de Konink, Charlotte; Deb, Wallid; Vignard, Virginie; Studencka-Turski, Maja; Besnard, Thomas; Hajdukowicz, Anna; Thiel, Franziska; Wolfgramm, Sophie; Florenceau, Laëtitia; Cuinat, Silvestre; Marsac, Sylvain; Verrès, Yann; Dangoumau, Audrey; Poirier, Léa; Wentzensen, Ingrid; Tuttle, Annabelle; Forster, Cara; Striesow, Johanna; Golnik, Richard; Ortiz, Damara; Jenkins, Laura; Rosenfeld, Jill; Ziegler, Alban; Houdayer, Clara; Bonneau, Dominique; Torti, Erin; Begtrup, Amber; Monaghan, Kristin; Mullegama, Sureni; Volker-Touw, Catharina; van Gassen, Koen; Oegema, Renske; de Pagter, Mirjam; Steindl, Katharina; Rauch, Anita; Ivanovski, Ivan; Mcdonald, Kimberly; Boothe, Emily; Dauber, Andrew; Baker, Janice; Fabie, Noelle Andrea V.; Bernier, Raphael; Turner, Tychele; Srivastava, Siddharth; Dies, Kira; Swanson, Lindsay; Costin, Carrie; Abdulrazak, Alali; Jobling, Rebekah; Pappas, John; Rabin, Rachel; Niyazov, Dmitriy; Chun-Hui Tsai, Anne; Kovak, Karen; Beck, David; Malicdan, May Christine V.; Adams, David; Wolfe, Lynne; Ganetzky, Rebecca; Muraresku, Colleen; Babikyan, Davit; Sedláček, Zdeněk; Hančárová, Miroslava; Timberlake, Andrew; Saif, Hind Al; Nestler, Berkley; King, Kayla; Hajianpour, Mj; Costain, Gregory; Prendergast, D’arcy; Li, Chumei; Geneviève, David; Vitobello, Antonio; Sorlin, Arthur; Philippe, Christophe; Harel, Tamar; Toker, Ori; Sabir, Ataf; Lim, Derek; Hamilton, Mark; Bryson, Lisa; Cleary, Elaine; Weber, Sacha; Hoffman, Trevor; Cueto-González, Anna; Tizzano, Eduardo; Gómez-Andrés, David; Codina-Solà, Marta; Ververi, Athina; Pavlidou, Efterpi; Lambropoulos, Alexandros; Garganis, Kyriakos; Rio, Marlène; Levy, Jonathan; Langas, Sarah; Mcrae, Anne; Lessard, Mathieu; D’agostino, Maria Daniela; de Bie, Isabelle; Wegler, Meret; Abou Jamra, Rami; Kamphausen, Susanne; Bothe, Viktoria; Potocki, Lorraine; Olinger, Eric; Sznajer, Yves; Wiame, Elsa; Thompson, Michelle; Schroeder, Molly; Gooch, Catherine; Smith, Raphael; Pandya, Arti; Busch, Larissa; Völker, Uwe; Hammer, Elke; Wende, Kristian; Cogné, Benjamin; Isidor, Bertrand; Meiler, Jens; Ripoll, Clémentine; Bigou, Stéphanie; Laumonnier, Frédéric; Hildebrand, Peter; Eichler, Evan; Mcwalter, Kirsty; Krawitz, Peter; Roux-Dalvai, Florence; Elgersma, Ype; Marcoux, Julien; Bousquet, Marie-Pierre; Droit, Arnaud; Poschmann, Jeremie; Grabrucker, Andreas; Bolduc, Francois; Bézieau, Stéphane; Ebstein, Frédéric; Krüger, Elke |
| Contributors: |
Centre Hospitalier Universitaire de Nantes = Nantes University Hospital (CHU Nantes); ITX-lab unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX-lab); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE); Nantes Université - pôle Santé; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé; Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ); School of Engineering Limerick, Ireland (Bernal Institute); University of Limerick (UL)-Bernal Institute Limerick, Ireland; University of Limerick (UL); Erasmus University Medical Center Rotterdam (Erasmus MC); Expertise Center for Neurodevelopmental Disorders Rotterdam, the Netherlands (ENCORE); Institut de pharmacologie et de biologie structurale (IPBS); Centre National de la Recherche Scientifique (CNRS)-Université de Toulouse (EPE UT); Communauté d'universités et établissements de Toulouse (Comue de Toulouse)-Communauté d'universités et établissements de Toulouse (Comue de Toulouse); Fédération de Recherche nationale ProFI (FR ProFI); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS); Rheinische Friedrich-Wilhelms-Universität Bonn; Institut de Transplantation et de Recherche en Transplantation CHU Nantes (ITERT); University of Alberta; Centre de recherche du CHU de Québec-Université Laval (CRCHUQ); CHU de Québec–Université Laval; Université Laval Québec (ULaval)-Université Laval Québec (ULaval); Leipzig University / Universität Leipzig; Washington University School of Medicine in St. Louis; Washington University in Saint Louis (WUSTL); Central South University Changsha; Universität Greifswald = University of Greifswald; Institut du Thorax CHU Nantes (CHU Thorax); Université de Toulouse (EPE UT); Communauté d'universités et établissements de Toulouse (Comue de Toulouse); ANR-21-CE17-0005,UPS-NDDecipher,Recherche translationnelle sur les maladies neurodéveloppementales causés par une déficience du système ubiquitine-protéasome(2021); ANR-22-RAR4-0001,UPS-NDDiag,Development of diagnostic solutions for neurodevelopmental disorders caused by ubiquitin-proteasome system dysfunction(2022); European Project: 825575,H2020-SC1-BHC-2018-2020,H2020-SC1-2018-Single-Stage-RTD,EJP RD(2019) |
| Source: |
ISSN: 2041-1723. |
| Publisher Information: |
CCSD; Nature Publishing Group |
| Publication Year: |
2025 |
| Collection: |
Université Toulouse III - Paul Sabatier: HAL-UPS |
| Subject Terms: |
[SDV]Life Sciences [q-bio] |
| Description: |
International audience ; 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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/grantAgreement//825575/EU/European Joint Programme on Rare Diseases/EJP RD |
| DOI: |
10.1038/s41467-025-65556-8 |
| Availability: |
https://hal.science/hal-05395426; https://hal.science/hal-05395426v1/document; https://hal.science/hal-05395426v1/file/s41467-025-65556-8.pdf; https://doi.org/10.1038/s41467-025-65556-8 |
| Rights: |
https://creativecommons.org/licenses/by/4.0/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.A848CE20 |
| Database: |
BASE |