揭示蛋白酶体ATP酶亚基基因在神经发育性蛋白酶体病中的关键神经元作用。
Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene in neurodevelopmental proteasomopathies.
作者信息
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
出版信息
medRxiv. 2024 Jan 26:2024.01.13.24301174. doi: 10.1101/2024.01.13.24301174.
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 , which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. Overexpression of variants altered human hippocampal neuron morphology, while knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons. 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.
神经发育蛋白酶体病是一类独特的神经发育障碍（NDD），其特征是26S蛋白酶体存在基因变异，26S蛋白酶体是一种控制真核细胞蛋白质稳态的蛋白质复合物。在我们的综合研究中，我们在编码AAA-ATP酶蛋白酶体亚基PSMC5/Rpt6的基因中鉴定出23种独特变异，这些变异在38名无亲缘关系的个体中导致了综合征性NDD。这些变异的过表达改变了人类海马神经元的形态，而该基因的敲低导致果蝇逆向学习受损以及大鼠海马神经元兴奋性突触丧失。该基因功能丧失导致异常蛋白质聚集，严重影响受影响个体的先天免疫信号传导、线粒体自噬率和脂质代谢。重要的是，靶向综合应激反应的关键成分，如PKR和GCN2激酶，可改善受影响个体细胞中的免疫失调。这些发现显著推进了我们对神经发育蛋白酶体病潜在分子机制的理解，为神经退行性疾病的研究提供了联系，并开辟了潜在的治疗途径。
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