Research Information System University of Greifswald

Küry S*, Stanton J, van Woerden G, Bosc-Rosati A, Hsieh T, Bray L, Oloudé M, Rosenfelt C, Scott-Boyer M, Most V, Wang T, Papendorf J¹, de Konink C, Deb W, Vignard V, Studencka-Turski M¹, Besnard T, Hajdukowicz A¹, Thiel F¹, Wolfgramm S¹, Florenceau L, Cuinat S, Marsac S, Verrès Y, Dangoumau A, Poirier L, Wentzensen I, Tuttle A, Forster C, Striesow J, Golnik R, Ortiz D, Jenkins L, Rosenfeld J, Ziegler A, Houdayer C, Bonneau D, Torti E, Begtrup A, Monaghan K, Mullegama S, Nienke Volker-Touw C, van Gassen K, Oegema R, de Pagter M, Steindl K, Rauch A, Ivanovski I, McDonald K, Boothe E, Dauber A, Baker J, Fabie N, Bernier R, Turner T, Srivastava S, Dies K, Swanson L, Costin C, Abdulrazak A, Jobling R, Pappas J, Rabin R, Niyazov D, Tsai A, Kovak K, Beck D, Malicdan M, Adams D, Wolfe L, Ganetzky R, Muraresku C, Babikyan D, Sedláček Z, Hančárová M, Timberlake A, Al Saif H, Nestler B, King K, Hajianpour M, Costain G, Prendergast D, Li C, Geneviève D, Vitobello A, Sorlin A, Philippe C, Harel T, Toker O, Sabir A, Lim D, Hamilton M, Bryson L, Cleary E, Weber S, Hoffman T, Cueto-González A, Tizzano E, Gómez-Andrés D, Codina-Solà M, Ververi A, Pavlidou E, Lambropoulos A, Garganis K, Rio M, Levy J, Langas S, McRae A, Lessard M, D'Agostino M, De Bie I, Wegler M, Abou Jamra R, Kamphausen S, Bothe V, Potocki L, Olinger E, Sznajer Y, Wiame E, Thompson M, Schroeder M, Gooch C, Smith R, Pandya A, Busch L², Völker U², Hammer E², Wende K, Cogné B, Isidor B, Meiler J, Ripoll C, Bigou S, Laumonnier F, Hildebrand P, Eichler E, McWalter K, Krawitz P, Roux-Dalvai F, Elgersma Y, Marcoux J, Bousquet M, Droit A, Poschmann J, Grabrucker A, Bolduc F, Bézieau S, Ebstein F¹, Krüger E¹

1 - Institut für Medizinische Biochemie und Molekularbiologie

2 - Interfakultäres Institut für Genetik und Funktionelle Genomforschung / Abt. Funktionelle Genomforschung

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.