Медицинская библиотека · Nature communications · 2025
Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.
Küry Sébastien, Stanton Janelle E, van Woerden Geeske M, Bosc-Rosati Amélie, Hsieh Tzung-Chien, Bray Lise, Oloudé Marielle, Rosenfelt Cory, Scott-Boyer Marie Pier, Most Victoria, Wang Tianyun, Papendorf Jonas J, de Konink Charlotte, Deb Wallid, Vignard Virginie, Studencka-Turski Maja, Besnard Thomas, Hajdukowicz Anna M, Thiel Franziska G, Wolfgramm Sophie, Florenceau Laëtitia, Cuinat Silvestre, Marsac Sylvain, Verrès Yann, Dangoumau Audrey, Poirier Léa, Wentzensen Ingrid M, 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 Catharina M L Nienke, van Gassen Koen L I, Oegema Renske, de Pagter Mirjam S, 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 C, Costin Carrie, Abdulrazak Alali, Jobling Rebekah K, Pappas John, Rabin Rachel, Niyazov Dmitriy, Chun-Hui Tsai Anne, Kovak Karen, Beck David B, Malicdan May Christine V, Adams David R, Wolfe Lynne, Ganetzky Rebecca D, Muraresku Colleen C, Babikyan Davit, Sedláček Zdeněk, Hančárová Miroslava, Timberlake Andrew T, Saif Hind Al, 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 J, Bryson Lisa J, Cleary Elaine, Weber Sacha, Hoffman Trevor L, Cueto-González Anna M, Tizzano Eduardo F, Gómez-Andrés David, Codina-Solà Marta, Ververi Athina, Pavlidou Efterpi, Lambropoulos Alexandros, Garganis Kyriakos, Rio Marlène, Levy Jonathan, Langas Sarah J, McRae Anne M, Lessard Mathieu K, D'Agostino Maria Daniela, De Bie Isabelle, Wegler Meret, Abou Jamra Rami, Kamphausen Susanne B, Bothe Viktoria, Potocki Lorraine, Olinger Eric, Sznajer Yves, Wiame Elsa, Thompson Michelle L, Schroeder Molly C, Gooch Catherine, Smith Raphael A, Pandya Arti, Busch Larissa M, Völker Uwe, Hammer Elke, Wende Kristian, Cogné Benjamin, Isidor Bertrand, Meiler Jens, Ripoll Clémentine, Bigou Stéphanie, Laumonnier Frédéric, Hildebrand Peter W, Eichler Evan E, McWalter Kirsty, Krawitz Peter M, Roux-Dalvai Florence, Elgersma Ype, Marcoux Julien, Bousquet Marie-Pierre, Droit Arnaud, Poschmann Jeremie, Grabrucker Andreas M, Bolduc Francois V, Bézieau Stéphane, Ebstein Frédéric, Krüger Elke
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Аннотация
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.
Для цитирования: Küry Sébastien, Stanton Janelle E, van Woerden Geeske M, Bosc-Rosati Amélie, Hsieh Tzung-Chien, Bray Lise, Oloudé Marielle, Rosenfelt Cory, Scott-Boyer Marie Pier, Most Victoria, Wang Tianyun, Papendorf Jonas J, de Konink Charlotte, Deb Wallid, Vignard Virginie, Studencka-Turski Maja, Besnard Thomas, Hajdukowicz Anna M, Thiel Franziska G, Wolfgramm Sophie, Florenceau Laëtitia, Cuinat Silvestre, Marsac Sylvain, Verrès Yann, Dangoumau Audrey, Poirier Léa, Wentzensen Ingrid M, 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 Catharina M L Nienke, van Gassen Koen L I, Oegema Renske, de Pagter Mirjam S, 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 C, Costin Carrie, Abdulrazak Alali, Jobling Rebekah K, Pappas John, Rabin Rachel, Niyazov Dmitriy, Chun-Hui Tsai Anne, Kovak Karen, Beck David B, Malicdan May Christine V, Adams David R, Wolfe Lynne, Ganetzky Rebecca D, Muraresku Colleen C, Babikyan Davit, Sedláček Zdeněk, Hančárová Miroslava, Timberlake Andrew T, Saif Hind Al, 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 J, Bryson Lisa J, Cleary Elaine, Weber Sacha, Hoffman Trevor L, Cueto-González Anna M, Tizzano Eduardo F, Gómez-Andrés David, Codina-Solà Marta, Ververi Athina, Pavlidou Efterpi, Lambropoulos Alexandros, Garganis Kyriakos, Rio Marlène, Levy Jonathan, Langas Sarah J, McRae Anne M, Lessard Mathieu K, D'Agostino Maria Daniela, De Bie Isabelle, Wegler Meret, Abou Jamra Rami, Kamphausen Susanne B, Bothe Viktoria, Potocki Lorraine, Olinger Eric, Sznajer Yves, Wiame Elsa, Thompson Michelle L, Schroeder Molly C, Gooch Catherine, Smith Raphael A, Pandya Arti, Busch Larissa M, Völker Uwe, Hammer Elke, Wende Kristian, Cogné Benjamin, Isidor Bertrand, Meiler Jens, Ripoll Clémentine, Bigou Stéphanie, Laumonnier Frédéric, Hildebrand Peter W, Eichler Evan E, McWalter Kirsty, Krawitz Peter M, Roux-Dalvai Florence, Elgersma Ype, Marcoux Julien, Bousquet Marie-Pierre, Droit Arnaud, Poschmann Jeremie, Grabrucker Andreas M, Bolduc Francois V, Bézieau Stéphane, Ebstein Frédéric, Krüger Elke. Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.. Nature communications. 2025. DOI: 10.1038/s41467-025-65556-8.
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