汉堡-埃彭多夫大学Manuel A. Friese课题组取得一项新突破。他们的最新研究揭示了在多发性硬化症中，免疫蛋白酶体干扰神经元代谢并驱动神经变性。该项研究成果发表在2025年6月17日出版的《细胞》上。
通过对炎症神经元中蛋白酶体亚基的转录、蛋白质组学和功能分析，课题组人员发现干扰素-γ介导的免疫蛋白酶体亚基蛋白酶体20S β 8 （PSMB8）的诱导会损害蛋白酶体平衡，导致蛋白酶体活性降低。这种减少导致磷酸果糖-2-激酶/果糖-2,6-二磷酸酶3 （PFKFB3）的积累，这是一种关键的代谢调节因子，导致神经元糖酵解增强，戊糖磷酸途径活性降低，氧化损伤和铁死亡。他们的发现为多发性硬化症和其他可能的神经退行性疾病的蛋白酶体功能障碍提供了统一的解释，将炎症与代谢破坏联系起来，并为靶向神经保护治疗提供了机会。
据了解，炎症、异常蛋白酶抑制和能量消耗是多发性硬化症（MS）等神经退行性疾病的标志。然而，炎症、神经元蛋白酶体功能障碍及其对神经元完整性的影响之间的相互作用尚不清楚。
附：英文原文
Title: The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis
Author: Marcel S. Woo, Johannes Brand, Lukas C. Bal, Manuela Moritz, Mark Walkenhorst, Vanessa Vieira, Inbal Ipenberg, Nicola Rothammer, Man Wang, Batuhan Dogan, Desirée Loreth, Christina Mayer, Darwin Nagel, Ingrid Wagner, Lena Kristina Pfeffer, Peter Landgraf, Marco van Ham, Kuno M.-J. Mattern, Ingo Winschel, Noah Frantz, Jana K. Sonner, Henrike K. Grosshans, Albert Miguela, Simone Bauer, Nina Meurs, Anke Müller, Lars Binkle-Ladisch, Gabriela Salinas, Lothar Jnsch, Daniela C. Dieterich, Maria Riedner, Elke Krüger, Frank L. Heppner, Markus Glatzel, Victor G. Puelles, Jan Broder Engler, Jens Randel Nyengaard, Thomas Misgeld, Martin Kerschensteiner, Doron Merkler, Catherine Meyer-Schwesinger, Manuel A. Friese
Issue&Volume: 2025-06-17
Abstract: Inflammation, aberrant proteostasis, and energy depletion are hallmarks of neurodegenerative diseases such as multiple sclerosis (MS). However, the interplay between inflammation, proteasomal dysfunction in neurons, and its consequences for neuronal integrity remains unclear. Using transcriptional, proteomic, and functional analyses of proteasomal subunits in inflamed neurons, we found that interferon-γ-mediated induction of the immunoproteasome subunit, proteasome 20S beta 8 (PSMB8) impairs the proteasomal balance, resulting in reduced proteasome activity. This reduction causes the accumulation of phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key metabolic regulator, leading to enhanced neuronal glycolysis, reduced pentose phosphate pathway activity, oxidative injury, and ferroptosis. Neuron-specific genetic and systemic pharmacological targeting of PSMB8 or PFKFB3 protected neurons in vitro and in a mouse model of MS. Our findings provide a unifying explanation for proteasomal dysfunction in MS and possibly other neurodegenerative diseases, linking inflammation to metabolic disruption, and presenting an opportunity for targeted neuroprotective therapies.
DOI: 10.1016/j.cell.2025.05.029
Source: https://www.cell.com/cell/abstract/S0092-8674(25)00616-6