| Title: |
Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene PSMC5 in 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,M J; 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; Genetica Sectie Genoomdiagnostiek; Child Health; Genetica Klinische Genetica; Brain |
| Publisher Information: |
medRxiv |
| Publication Year: |
2024 |
| Description: |
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. |
| Document Type: |
other/unknown material |
| Language: |
English |
| Relation: |
https://dspace.library.uu.nl/handle/1874/469662 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/469662 |
| Rights: |
info:eu-repo/semantics/ClosedAccess |
| Accession Number: |
edsbas.77D86C50 |
| Database: |
BASE |