Unveiling the crucial neuronal role of the proteasomal ATPase subunit genePSMC5in neurodevelopmental proteasomopathies
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 , Deb Wallid , Vignard Virginie , Studencka-Turski Maja , Besnard Thomas , Hajdukowicz Anna Marta , Thiel Franziska , Möller Sophie , Florenceau Laëtitia , Cuinat Silvestre , Marsac Sylvain , Wentzensen Ingrid , Tuttle Annabelle , Forster Cara , Striesow Johanna , Golnik Richard , Ortiz Damara , Jenkins Laura , Rosenfeld Jill A. , Ziegler Alban , Houdayer Clara , Bonneau Dominique , Torti Erin , Begtrup Amber , Monaghan Kristin G. , Mullegama Sureni V. , Volker-Touw C.M.L. (Nienke) , van Gassen Koen L. I. , 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 A. , Turner Tychele N. , Srivastava Siddharth , Dies Kira A. , Swanson Lindsay , Costin Carrie , Jobling Rebekah K. , Pappas John , Rabin Rachel , Niyazov Dmitriy , Tsai Anne Chun-Hui , Kovak Karen , Beck David B. , Malicdan MCV , Adams David R. , Wolfe Lynne , Ganetzky Rebecca D. , Muraresku Colleen , Babikyan Davit , Sedláček Zdeněk , Hančárová Miroslava , Timberlake Andrew T. , Al Saif Hind , 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 L. , Cueto-González Anna Maria , Tizzano Eduardo Fidel , Gómez-Andrés David , Codina-Solà Marta , Ververi Athina , Pavlidou Efterpi , Lambropoulos Alexandros , Garganis Kyriakos , Rio Marlène , Levy Jonathan , Jurgensmeyer Sarah , McRae Anne M. , Lessard Mathieu Kent , D’Agostino Maria Daniela , De Bie Isabelle , Wegler Meret , Jamra Rami Abou , Kamphausen Susanne B. , Bothe Viktoria , Busch Larissa M. , Völker Uwe , Hammer Elke , Wende Kristian , Cogné Benjamin , Isidor Bertrand , Meiler Jens , Bosc-Rosati Amélie , Marcoux Julien , Bousquet Marie-Pierre , Poschmann Jeremie , Laumonnier Frédéric , Hildebrand Peter W. , Eichler Evan E. , McWalter Kirsty , Krawitz Peter M. , Droit Arnaud , Elgersma Ype , Grabrucker Andreas M. , Bolduc Francois V. , Bézieau Stéphane , Ebstein Frédéric , Krüger Elke 
Published: January 2024

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 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.