Unveiling the crucial neuronal role of the proteasomal ATPase subunit genePSMC5in neurodevelopmental proteasomopathies
Author:
Küry SébastienORCID, Stanton Janelle E.ORCID, van Woerden GeeskeORCID, Hsieh Tzung-ChienORCID, Rosenfelt CoryORCID, Scott-Boyer Marie PierORCID, Most VictoriaORCID, Wang Tianyun, Papendorf Jonas Johannes, de Konink CharlotteORCID, Deb WallidORCID, Vignard VirginieORCID, Studencka-Turski MajaORCID, Besnard ThomasORCID, Hajdukowicz Anna Marta, Thiel Franziska, Möller Sophie, Florenceau Laëtitia, Cuinat SilvestreORCID, Marsac Sylvain, Wentzensen IngridORCID, Tuttle AnnabelleORCID, Forster Cara, Striesow JohannaORCID, Golnik RichardORCID, Ortiz Damara, Jenkins Laura, Rosenfeld Jill A.ORCID, Ziegler Alban, Houdayer Clara, Bonneau DominiqueORCID, Torti ErinORCID, Begtrup AmberORCID, Monaghan Kristin G.ORCID, Mullegama Sureni V., Volker-Touw C.M.L. (Nienke), van Gassen Koen L. I.ORCID, Oegema RenskeORCID, de Pagter MirjamORCID, Steindl KatharinaORCID, Rauch AnitaORCID, Ivanovski Ivan, McDonald KimberlyORCID, Boothe Emily, Dauber AndrewORCID, Baker Janice, Fabie Noelle Andrea V, Bernier Raphael A.ORCID, Turner Tychele N.ORCID, Srivastava Siddharth, Dies Kira A.ORCID, Swanson Lindsay, Costin Carrie, Jobling Rebekah K.ORCID, Pappas JohnORCID, Rabin RachelORCID, Niyazov DmitriyORCID, Tsai Anne Chun-HuiORCID, Kovak Karen, Beck David B., Malicdan MCVORCID, Adams David R., Wolfe Lynne, Ganetzky Rebecca D.ORCID, Muraresku Colleen, Babikyan DavitORCID, Sedláček ZdeněkORCID, Hančárová MiroslavaORCID, Timberlake Andrew T.ORCID, Al Saif Hind, Nestler Berkley, King Kayla, Hajianpour MJORCID, Costain GregoryORCID, Prendergast D’Arcy, Li Chumei, Geneviève DavidORCID, Vitobello AntonioORCID, Sorlin ArthurORCID, Philippe Christophe, Harel TamarORCID, Toker Ori, Sabir AtafORCID, Lim Derek, Hamilton Mark, Bryson Lisa, Cleary Elaine, Weber Sacha, Hoffman Trevor L., Cueto-González Anna Maria, Tizzano Eduardo Fidel, Gómez-Andrés DavidORCID, Codina-Solà MartaORCID, Ververi AthinaORCID, Pavlidou EfterpiORCID, Lambropoulos Alexandros, Garganis Kyriakos, Rio MarlèneORCID, Levy Jonathan, Jurgensmeyer SarahORCID, McRae Anne M.ORCID, Lessard Mathieu Kent, D’Agostino Maria DanielaORCID, De Bie IsabelleORCID, Wegler MeretORCID, Jamra Rami AbouORCID, Kamphausen Susanne B., Bothe ViktoriaORCID, Busch Larissa M.ORCID, Völker Uwe, Hammer ElkeORCID, Wende KristianORCID, Cogné Benjamin, Isidor BertrandORCID, Meiler JensORCID, Bosc-Rosati Amélie, Marcoux JulienORCID, Bousquet Marie-PierreORCID, Poschmann JeremieORCID, Laumonnier FrédéricORCID, Hildebrand Peter W.ORCID, Eichler Evan E.ORCID, McWalter KirstyORCID, Krawitz Peter M.ORCID, Droit ArnaudORCID, Elgersma YpeORCID, Grabrucker Andreas M.ORCID, Bolduc Francois V.ORCID, Bézieau StéphaneORCID, Ebstein FrédéricORCID, Krüger ElkeORCID
Abstract
AbstractNeurodevelopmental 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 inPSMC5, which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. Overexpression ofPSMC5variants altered human hippocampal neuron morphology, whilePSMC5knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons.PSMC5loss-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.
Publisher
Cold Spring Harbor Laboratory
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