Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.
Publication date
2024-01-26
Authors
Küry, Sébastien
Stanton, Janelle E
van Woerden, Geeske
Hsieh, Tzung-Chien
Rosenfelt, Cory
Scott-Boyer, Marie Pier
Most, Victoria
Wang, Tianyun
Papendorf, Jonas Johannes
de Konink, Charlotte
Editors
Advisors
Supervisors
Document Type
/dk/atira/pure/researchoutput/researchoutputtypes/workingpaper/preprint
Metadata
Show full item recordCollections
License
Abstract
Neurodevelopmental proteasomopathies represent a distinctive category of neurodevelopmental disorders (NDD) characterized by genetic variations within the 26S proteasome, a protein complex governing eukaryotic cellular protein homeostasis. In our comprehensive study, we identified 23 unique variants in PSMC5 , which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. Overexpression of PSMC5 variants altered human hippocampal neuron morphology, while PSMC5 knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons. PSMC5 loss-of-function resulted in abnormal protein aggregation, profoundly impacting innate immune signaling, mitophagy rates, and lipid metabolism in affected individuals. Importantly, targeting key components of the integrated stress response, such as PKR and GCN2 kinases, ameliorated immune dysregulations in cells from affected individuals. These findings significantly advance our understanding of the molecular mechanisms underlying neurodevelopmental proteasomopathies, provide links to research in neurodegenerative diseases, and open up potential therapeutic avenues.
Keywords
Citation
Küry, S, Stanton, J E, van Woerden, G, Hsieh, T-C, Rosenfelt, C, Scott-Boyer, M P, Most, V, Wang, T, Papendorf, J J, de Konink, C, Deb, W, Vignard, V, Studencka-Turski, M, Besnard, T, Hajdukowicz, A M, Thiel, F, Möller, S, Florenceau, L, Cuinat, S, Marsac, S, Wentzensen, I, Tuttle, A, Forster, C, Striesow, J, Golnik, R, Ortiz, D, Jenkins, L, Rosenfeld, J A, Ziegler, A, Houdayer, C, Bonneau, D, Torti, E, Begtrup, A, Monaghan, K G, Mullegama, S V, Volker-Touw, C M L N, van Gassen, K L I, Oegema, R, de Pagter, M, Steindl, K, Rauch, A, Ivanovski, I, McDonald, K, Boothe, E, Dauber, A, Baker, J, Fabie, N A V, Bernier, R A, Turner, T N, Srivastava, S, Dies, K A, Swanson, L, Costin, C, Jobling, R K, Pappas, J, Rabin, R, Niyazov, D, Tsai, A C-H, Kovak, K, Beck, D B, Malicdan, M, Adams, D R, Wolfe, L, Ganetzky, R D, Muraresku, C, Babikyan, D, Sedláček, Z, Hančárová, M, Timberlake, A T, Al Saif, H, Nestler, B, King, K, Hajianpour, M J, Costain, G, Prendergast, DA, 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 L, Cueto-González, A M, Tizzano, E F, Gómez-Andrés, D, Codina-Solà, M, Ververi, A, Pavlidou, E, Lambropoulos, A, Garganis, K, Rio, M, Levy, J, Jurgensmeyer, S, McRae, A M, Lessard, M K, D'Agostino, M D, De Bie, I, Wegler, M, Jamra, R A, Kamphausen, S B, Bothe, V, Busch, L M, Völker, U, Hammer, E, Wende, K, Cogné, B, Isidor, B, Meiler, J, Bosc-Rosati, A, Marcoux, J, Bousquet, M-P, Poschmann, J, Laumonnier, F, Hildebrand, P W, Eichler, E E, McWalter, K, Krawitz, P M, Droit, A, Elgersma, Y, Grabrucker, A M, Bolduc, F V, Bézieau, S, Ebstein, F & Krüger, E 2024 'Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.' medRxiv. https://doi.org/10.1101/2024.01.13.24301174