Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies
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.
Article Details
Authors (149)
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
Department of Medical Genetics, School of Basic Medical Sciences, Neuroscience Research Institute, Key Laboratory for Neuroscience, Ministry of Education of China & National Health Commission of China, Peking University
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
MJ Hajianpour
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
Department of Functional Genomics, Universitätsmedizin Greifswald, Greifswald, Germany
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
Nantes Université, Centre Hospitalier Universitaire (CHU) Nantes, Centre National de la Recherche Scientifique (CNRS), INSERM, l’Institut du Thorax, Nantes, France
Frédéric Ebstein
Elke Krüger