Das Prodekanat für Forschung würdigt jeden Monat UKE Autorinnen und Autoren einer herausragenden Publikation, die in den vorangegangenen 2 Monaten hochrangig publiziert wurde. Ziel ist es, die am UKE enstandenen Forschungsergebnisse mit ihrer Bedeutung in der Wissenschaft einer größeren Öffentlichkeit am UKE vorzustellen. Der Aufruf zur Teilnahme richtet sich an Wissenschaftlerinnen und Wissenschaftler aller Fachgebiete. Einreichungsfrist für eine Bewerbung um die Auszeichnung des "Paper of the Month" ist jeweils Ende eines Monats (siehe Bewerbungsformular).
Das PoM-Archiv finden Sie hier:
UKE Paper of the Month June 2025
The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis
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 Jänsch, 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
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.
STATEMENT:
Our paper describes a novel framework how chronic inflammation causes key hallmarks of neurodegenerative diseases including protein accumulation and metabolic dysfunction. It identifies the immunoproteasome as a central component of the neuronal inflammatory stress response and as a central driver of inflammation-induced neurodegeneration that can be pharmacologically targeted.
BACKGROUND:
This work was mainly conducted at the Institute of Neuroimmunology and Multiple Sclerosis (INIMS) under the supervision of Prof. Manuel A. Friese and the Institute of Cellular and Integrative Physiology under the supervision of Prof. Catherine Meyer-Schwesinger, together with several UKE departments, as well as national and international collaborations. The project was part of the DFG-funded FOR5705 (FR 1720/29-1, ME 2108/15-1, GL 589/12-1, EN 1328/3-1 and KE 774/6-1). The project was also supported by the DFG SPP 2306 (FR 1720/30-1 and WO 2835/1-1). It was mostly performed by the Clinician Scientist Dr. Marcel S. Woo who is funded by the Else Kröner Memorial Fellowship of the Else Kröner-Fresenius-Stiftung (2023_EKMS.03)..
Cell. 2025 Jun 13:S0092-8674(25)00616-6.
Congratulations to all authors!
Next PoM: To apply, the publication must have been published in May2025. Applications will be considered in two rounds of the selection process, i.e. two months. Please send your completed PoM application to Dr. Anne Wulf by 31/07/2025.